Pediatric-onset Multiple Sclerosis Research Articles

Gene–environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals...

Family health conditions and parental occupational status modify the relationship between pediatric-onset multiple sclerosis and parental health-related quality of life

Background: The health-related quality of life (HRQoL) of children with multiple sclerosis (MS) is mediated by the HRQoL of their parents. Understanding factors that modify the relationship between the child’s MS diagnosis and parental HRQoL would inform interventions to improve the HRQoL of both parents and children living with MS. Objective: We evaluated whether the association between an MS diagnosis during childhood and parental HRQoL is modified by the presence of a family health condition or low socioeconomic position (SEP). Methods: Parents of children with MS or the transient illness, monophasic-acquired demyelinating syndromes (monoADS), were enrolled in a prospective Canadian study. Multivariable models evaluated whether the association between a child’s MS diagnosis (vs. monoADS) and parental HRQoL was modified by ⩾1 family health conditions or low SEP. Results: Two hundred seven parents and their children with MS (n = 65) or monoADS (n = 142) were included. We found a synergistic effect of an MS diagnosis and a family health condition on parental HRQoL. We also found a synergistic effect of having MS and a low SEP on parental HRQoL. Conclusion: Parents of children with MS who have another family health condition or a low SEP are at particularly high risk for low HRQoL.

Alemtuzumab following natalizumab is more effective in adult-onset than paediatric-onset multiple sclerosis.

Paediatric-onset multiple sclerosis (POMS) therapeutic approach derives from of adult-onset multiple sclerosis (AOMS) tailored algorithms. To evaluate in a common clinical scenario the efficacy and safety of alemtuzumab (ALZ) in POMS and AOMS. All patients switching from natalizumab (NTZ) to ALZ for safety concerns (high anti-John Cunningham Virus Antibody Index value, anti-JCV Index) were enrolled in this single-centre, retrospective, case-control open-label study. Ten POMS and 27 AOMS were followed up for 51.3 months. After month 12, we found a lower risk of clinical or radiological relapses among AOMS patients and among patients with older age at ALZ (both p < 0.05). Survival analysis revealed an increased risk of relapse in POMS compared with AOMS (logrank p = 0.00498) and patients starting ALZ before age 22.75 years than the elder ones (logrank p = 0.0018). Survival analysis did not disclose any difference between AOMS and POMS (logrank p = 0.27) in terms of progression independent of any relapse activity (PIRA). In addition, no evidence of relapse-associated worsening was observed. Autoimmune events were reported by 5 AOMS and no POMS (29.4% versus 0.0%, p = 0.057), and survival analysis was not significant (logrank p = 0.0786). ALZ seems more effective in AOMS than in POMS following NTZ. These findings underrate ALZ effectiveness when shifting from NTZ in POMS.

Clinical and Epidemiological Findings of Pediatric Onset Multiple Sclerosis in East-Azerbaijan, Iran; A Population-based Study.

Multiple sclerosis (MS) is among the most prevalent chronic immune-mediated inflammatory diseases. If MS onset is under 18, it is defined as pediatric-onset MS (POMS). This study aimed to determine the clinical and epidemiological aspects of POMS. This population-based study was conducted in East-Azerbaijan (EA) province and concerned POMS patients. The data concerning almost all of the POMS patients of the province was gathered from the only MS registry center in the university hospital of the Tabriz University of Medical Sciences by the end of 2017. The diagnosis of patients was based on McDonald's criteria. Out of 2976 total cases of MS, eighty-five (2.85%) were POMS. The overall regional prevalence of POMS was 11.67 per 100,000 (95% CI:9.43-11.43). Sixty-seven cases were female (prevalence: 18.94 per 100,000 [95% CI:14.91-24.07], and eighteen were male (prevalence: 4.80 per 100,000 [95% CI:3.03-7.62]. The crude regional incidence in 2017 was 1.37/100,000 (95% CI:0.74-2.55). The mean age of onset was 15.81±1.33 years, with a minimum age of 12. 71.76% of the patients were diagnosed in the 16- or 17-years old age group. 7.05% had a positive family history, and 87.5% of the patients diagnosed the disease promptly. The most common first clinical presentations were blurred vision (43.75%), sensory (28.12%), cerebellar (15.62%), and brainstem (9.37%) symptoms. POMS is not a rare condition, and it mainly affects females. POMS prevalence increases significantly after age 15 years old, and the first manifestation of the disease is usually blurred vision.

Narrative review based on fingolimod therapy in pediatric MS.

The course of pediatric-onset multiple sclerosis and adult multiple sclerosis shows some clinical differences. The rate of having a second attack after the first clinical event is 80% in children and around 45% in adults but the time to the second event is similar in all age groups. The pediatric group usually has a more aggressive onset than adults. On the other hand, a higher rate of complete recovery is observed in pediatric-onset multiple sclerosis after the first clinical event compared to the adult group. Despite a highly active initial disease course, pediatric-onset multiple sclerosis patients show a slower increase in disability than patients with adult-onset disease. This is thought to be due to greater remyelination capacity and plasticity of the developing brain. The management of pediatric-onset multiple sclerosis includes safety issues as well as effective disease control. In the pediatric-onset multiple sclerosis group, similar to adult multiple sclerosis, injectable treatments have been used for many years with reasonable efficacy and safety. Since 2011, oral treatments and then infusion treatments have been approved and used effectively in adult multiple sclerosis and have gradually entered clinical use in the pediatric-onset multiple sclerosis group. However, clinical trials are fewer, smaller, and include shorter follow-up due to the much lower prevalence of pediatric-onset multiple sclerosis than adult multiple sclerosis. This is particularly important in the era of recent disease-modifying treatments. This review of the literature presents existing data on the safety and efficacy of fingolimod, pointing to a relatively favorable profile.

Analysis of determinants of treatment change in adult paediatric-onset MS patients.

Paediatric-onset multiple sclerosis (POMS) is increasing worldwide and represents approximately 5% of all MS cases. Although this patient group has similar characteristics to the adult group, it is important for this patient group to receive effective treatment due to the early onset of cognitive involvement, higher lesion burden, and secondary progression at an earlier age than adults. In this study, we aimed to evaluate the factors that cause treatment change in POMS patients. Adult patients with a first MS attack at age 18 years or younger who were followed up with the diagnosis of MS at the Clinical Neuroimmunology and Demyelinating Diseases outpatient clinic of Cerrahpaşa Medical School between 1987 and 2020 were included in our study. Patient files were reviewed retrospectively, and demographic and clinical characteristics, imaging, first attack characteristics, and treatment change were noted. We included 269 patients with a definite diagnosis of MS in the study, and these patients were evaluated in two groups: negative for treatment change and positive for treatment change. Multifocal involvement was detected more frequently in the group with treatment change (p=0,049). Cerebellar involvement as a first attack symptom was more common in male patients (p=0,023) The age at first MS attack was found to be younger (p=0,006), and the disease duration was longer in the positive for treatment change group (p=0,003). Spinal cord involvement was more common in the positive for treatment change group (p=0,016). Abnormal VEP findings were observed more frequently in the group without treatment change (p=0.018). In multivariant analysis, spinal cord involvement, younger age at first attack, and abnormal VEP findings in the group without treatment change were found to be significant. Among the reasons for treatment change, the most common reason was radiological and clinical progression. The higher inflammatory load in POMS patients compared with adults necessitates early initiation of treatment in this group and timely treatment change to prevent disability. Furthermore, this patient group should be followed closely and receive effective treatment.

Microbiomes and Pediatric onset multiple sclerosis (MS): A systematic review.

Gut microbiomes play a role in developing and regulating autoimmune diseases such as multiple sclerosis (MS). We designed this systematic review to summarize the evidence of the effect of gut microbiota in developing pediatric-onset MS. PubMed, Scopus, EMBASE, Web of Science, Google Scholar, references of the references and conference abstracts were comprehensively searched by two independent researchers. The search was done on January 1st, 2023. Data regarding the total number of patients, the name of the first author, publication year, country of origin, mean age, duration of the disease, body mass index (BMI), type of MS, Expanded Disability Status Scale (EDSS), age at disease onset and stool composition were extracted. A literature search revealed 4237 published studies. After removing duplicates, we had 2045 records for evaluation. Twenty-three full texts were evaluated, and four case-control studies remained for systematic review. Three studies were conducted in the United States and one in the Netherlands. The number of participants in included studies ranged between 24 and 68. The mean age of patients at the time of study varied between 11.9 and 17.9 years, and the mean age at the onset of the disease ranged between 11.5 and 14.3 years. Most included patients were female. The results show that median richness (the number of unique taxa identified, which was provided by two studies) was higher in controls, and also Margalef index, which was reported by one study was higher in control group than the case group. The results of two studies also demonstrated that median evenness indexes (taxon distribution, Shannon, Simpson) were higher in control groups, as well as PD index (Faith's phylogenic diversity metric). The result of this systematic review (including four studies) showed disruption of the microbiota-immune balance in pediatric-onset MS cases.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis

Background: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. Objective: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. Methods: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. Results: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (−0.26 nU, p = 0.0023), and in both in the ON (−0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (−0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). Conclusions: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

The Clinical and Epidemiological Profile of Paediatric-Onset Multiple Sclerosis in Poland.

Paediatric-onset MS (POMS) has a unique clinical profile compared to the more prevalent adult-onset MS. For this study, we aimed to determine the demographic and clinical characteristics of POMS in Poland as well as addressing some of its epidemiological aspects. A retrospective study was conducted based on the Polish Multiple Sclerosis Registry, considering a population of children and adolescents with MS (age ≤ 18 years). Data were collected by all 13 centres across Poland specializing in diagnosing and treating POMS. The actual course of the disease and its clinical properties were compared between child (≤12 years) and juvenile (&gt;12 years) patients. MS onset and its prevalence were assessed at the end of 2019, stratified by age range. A total of 329 paediatric or juvenile patients (228 girls, 101 boys) with a clinically definite diagnosis of MS, in conformity with the 2017 McDonald Criteria, were enrolled. For 71 children (21.6%), the first symptoms appeared before the age of 12. The female: male ratio increased with age, amounting to 1:1 in the ≤12 years group and to 2.9:1 in the &gt;12 years group. In most cases, the disease had multi-symptomatic onset (31.3%), and its course was mostly of a relapsing-remitting character (95.7%). The initial Expanded Disability Status Score for both groups was 1.63 ± 1.1, whereas the annual relapse rate was 0.84 during the first 2 years. The time between the onset of symptoms and diagnosis was longer in the younger patients (8.2 ± 4.2 vs. 4.6 ± 3.6 months; p &lt; 0.005). On 31 December 2019, the age-adjusted prevalence standardized to the European standard population was 5.19/100,000 (95% CI, 4.64-5.78). Significantly higher prevalence was noted in the 13-18 years group (7.12; 95% CI, 6.64-7.86) than in the 9-12 years group (3.41; 95% CI, 2.98-3.86) and the &lt;9 years group (0.56; 95% CI, 0.46-0.64; p &lt; 0.001). POMS commencing at the age of ≤12 years is rare, differing significantly from the juvenile-onset and adult MS in terms of clinical characteristics, course, and incidence, as stratified by gender.

Multiple Sclerosis and MEN2 Neoplasia in a Female Patient: A Unique Co-Existence with Expanded Immunological Interest and Therapeutical Challenges, before and after Patient’s COVID-19 Infection

Multiple sclerosis (MS) and its various comorbidities that may be observed are of great interest due to the complexity of MS pathophysiology and all of the immunological changes that follow. The incidence of cancer in MS has been investigated for several years, as not only does it affect ongoing therapeutical decisions, but also, certain disease-modifying treatments (DMTs) may increase the risk of tumorigenesis. For the first time, we present a case of a female patient with pediatric-onset MS (POMS) and multiple endocrine neoplasia 2B (MEN2B) and analyze the immunological impact of these diseases on the therapeutical choice, under the umbrella of her COVID-19 infection and the SARS-CoV-2 pandemic as a whole. We also review the existing literature regarding the immunogenetic and immunological correlations between these two extremely rare diseases and discuss the most suitable treatment for our case, which seems to be an anti-CD20 agent due to a better outcome in putative MS worsening and tumor progression, when killer immunoglobulin-like receptors' (KIR) expression is reduced in natural killer (NK) cells. We also broaden our concerns on this comorbidity issue, at the same time focusing on the future research needed in this unexplored field of the comorbidity of MS and cancers.

The Impact of Highly Effective Treatment in Pediatric-Onset Multiple Sclerosis: A Case Series.

Pediatric-onset multiple sclerosis (POMS) is characterized by high inflammatory disease activity. Our aim was to describe the treatment sequencing and report the impact highly effective disease-modifying treatment (HET) had on disease activity. Five consecutive patients with POMS were administered HET following lower efficacy drug or as initial therapy. Data on treatment sequencing, relapses and MRIs were collected during the follow-up. Our patients had an average age of 13.8 years (range 9-17) at diagnosis and 13.4 years (range 9-16) at disease onset, and 2/5 (40%) POMS were female. The pre-treatment average annualized relapse rate was 1.6 (range 0.8-2.8), and the average follow-up length was 5 years (range 3-7). A total of 2/5 (40%) patients were stable on HET at initial therapy, and 3/5 (60%) required an escalation to more aggressive treatment, even if two of them had been put on HET as initial treatment. Four out of five patients (80%) had No Evidence of Disease Activity-3 status (NEDA-3) at an average follow-up of 3 years (range 2-5). It has been observed that in a recent time period all the cases had prompt diagnosis, early HET or escalation to HET with a good outcome in 80% of the cases.

Gut microbiota analysis in pediatric-onset multiple sclerosis compared to pediatric monophasic demyelinating syndromes and pediatric controls.

Gut microbiota dysbiosis may lead to proinflammatory conditions contributing to multiple sclerosis (MS) etiology. Pediatric-onset MS patients are close to biological disease onset and less exposed to confounders. Therefore, this study investigated gut microbiota composition and functional pathways in pediatric-onset MS, compared to monophasic acquired demyelinating syndromes (mADS) and healthy controls (HCs). Pediatric participants were selected from the Dutch national prospective cohort study including ADS patients and HCs <18 years old. Amplicon sequence variants (ASVs) were generated from sequencing the V3/4 regions of the 16S rRNA gene. Functional MetaCyc microbial pathways were predicted based on Enzyme Commission numbers. Gut microbiota composition (alpha/beta diversity and individual microbe abundance at ASV to phylum level) and predicted functional pathways were tested using nonparametric tests, permutational multivariate analysis of variance, and linear regression. Twenty-six pediatric-onset MS (24 with disease-modifying therapy [DMT]), 25 mADS, and 24 HC subjects were included. Alpha/beta diversity, abundance of individual resident microbes, and microbial functional features were not different between these participant groups. Body mass index (BMI) showed significant differences, with obese children having a lower alpha diversity (Chao1 Index p= 0.015, Shannon/Simpson Diversity Index p= 0.014/p= 0.023), divergent beta diversity (R2 = 3.7%, p= 0.013), and higher abundance of numerous individual resident microbes and functional microbial pathways. Previous results of gut microbiota composition and predicted functional features could not be validated in this Dutch pediatric-onset MS cohort using a more sensitive 16S pipeline, although it was limited by sample size and DMT use. Notably, several other host-related factors were found to associate with gut microbiota variation, especially BMI.

The Economic and Humanistic Burden of Pediatric-Onset Multiple Sclerosis.

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. Pediatric-onset MS (POMS), defined as onset of MS before 18 years of age, is estimated to account for 2% to 5% of the MS population worldwide. Objectives: To conduct a literature review focused on the healthcare resource utilization and cost as well as quality-of-life (QOL) outcomes among patients with POMS. Methods: We conducted a systematic literature review of English-language studies published after September 2010 in MEDLINE and Embase to describe the global economic healthcare resource utilization and costs and humanistic (QOL) burden in patients with POMS. Results: We found 11 studies that reported on healthcare resource utilization, cost, or insurance coverage and 36 studies that reported on QOL outcomes in patients with POMS. Patients with POMS had higher rates of primary care visits (1.41 [1.29-1.54]), hospital visits (10.74 [8.95-12.90]), and admissions (rate ratio, 4.27 [2.92-6.25];OR, 15.2 [12.0-19.1]) compared with healthy controls. Mean per-patient costs in the United States were $5907 across all settings per year of follow-up between 2002 and 2012; mean costs per hospital stay were $38 543 (in 2015 USD) between 2004 and 2013. Three studies reported psychosocial scores between 71.59 and 79.7, and 8 studies reported physical health scores between 74.62 to 82.75 using the Pediatric Quality of Life Measurement Model (PedsQLTM). Twelve studies used the PedsQL™ Multidimensional Fatigue Scale. Mean scores on the self-reported general fatigue scale ranged from 63.15 to 78.5. Quality-of-life scores were lower than those of healthy controls. Discussion: Our review presents a uniquely broad and recent overview of the global economic and humanistic burden of patients with POMS. Additional research on healthcare resource utilization and cost would provide a more robust understanding of the economic burden in this population. Conclusions: Healthcare resource utilization and costs are high in this population, and patients report reduced QOL and significant fatigue compared with healthy children and adolescents.

First-line disease modifying treatments in pediatric-onset multiple sclerosis in Greece: therapy initiation at more advanced age is the main cause of treatment failure, in a retrospective observational study, with a cohort from a single Multiple Sclerosis Center

ObjectivesLong-term immunomodulatory therapy of pediatric onset-multiple sclerosis (POMS) is based mainly on published case series and internationally agreed guidelines. Relevant studies in the Greek population are absent from the literature. The purpose of this study is to present data on the efficacy and safety of the 1st line immunomodulatory drugs in the treatment of POMS patients.Materials and methodsThe present study included 27 patients meeting the IPMSSG criteria for POMS and who are monitored at the outpatient clinic of the Multiple Sclerosis and Demyelinating Diseases Unit (MSDDU), of the 1st Neurological Department, University Hospital of Aeginition. All patients received 1st line immunomodulatory drugs as initial therapy. Clinical, laboratory, and imaging parameters of the disease were recorded before and after treatment.ResultsPost-treatment, a significant reduction of the relapse number (mean ± SD: 2.0 ± 1.0 vs 1.2 ± 1.6, p = 0.002), EDSS progression (mean ± SD: 1.5 ± 0.8 vs 0.9 ± 0.7, p = 0.005) and ARR (mean ± SD: 1.5 ± 0.7 vs 0.4 ± 0.5, p = 0.0001) was observed, while no changes were observed in the EDSS score, (mean ± SD: 1.8 ± 0.6 vs 1.9. 0.6, p = 0.60). Advanced age at treatment initiation increased the risk for drug discontinuation before 24 months of therapy (HR = 0.6, 95% CI (0.35–0.99), p = 0.04).ConclusionsMost pediatric patients are forced to switch to either more efficacious 1st line or 2nd line drugs. Additionally, our study suggests that older age at the time of the 1st line treatment initiation, contributes to earlier drug discontinuation.

MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p=0.044), younger age (mean=8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p=0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p=0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry

BackgroundEarly recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time.ObjectiveTo identify...

Effect of Dimethyl Fumarate vs Interferon β-1a in Patients With Pediatric-Onset Multiple Sclerosis

With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS. The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Patients were randomized to DMF or IFNβ-1a. The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a. This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated. ClinicalTrials.gov Identifier: NCT02283853.

Neurodegeneration and humoral response proteins in cerebrospinal fluid associate with pediatric-onset multiple sclerosis and not monophasic demyelinating syndromes in childhood

Background: Pediatric-onset multiple sclerosis (POMS) represents the earliest stage of disease pathogenesis. Investigating the cerebrospinal fluid (CSF) proteome in POMS may provide novel insights into early MS processes. Objective: To analyze CSF obtained from children at time of initial central nervous system (CNS) acquired demyelinating syndrome (ADS), to compare CSF proteome of those subsequently ascertained as having POMS versus monophasic acquired demyelinating syndrome (mADS). Methods: Patients were selected from two prospective pediatric ADS studies. Liquid chromatography–mass spectrometry (LC-MS) was performed in a Dutch discovery cohort (POMS n = 28; mADS n = 39). Parallel reaction monitoring–mass spectrometry (PRM-MS) was performed on selected proteins more abundant in POMS in a combined Dutch and Canadian validation cohort (POMS n = 48; mADS n = 106). Results: Discovery identified 5580 peptides belonging to 576 proteins; 58 proteins were differentially abundant with ⩾2 peptides between POMS and mADS, of which 28 more abundant in POMS. Fourteen had increased abundance in POMS with ⩾8 unique peptides. Five selected proteins were all confirmed within validation. Adjusted for age, 2 out of 5 proteins remained more abundant in POMS, that is, Carboxypeptidase E (CPE) and Semaphorin-7A (SEMA7A). Conclusion: This exploratory study identified several CSF proteins associated with POMS and not mADS, potentially reflecting neurodegeneration, compensatory neuroprotection, and humoral response in POMS. The proteins associated with POMS highly correlated with age at CSF sampling.

Evaluation of white matter microstructure in pediatric onset multiple sclerosis with diffusion compartment imaging.

Pediatric-onset multiple sclerosis (POMS) shows earlier axonal involvement and greater axonal loss than in adults. We aim to characterize the white matter (WM) microstructural changes in POMS using a diffusion compartment imaging (DCI) model and compare it to standard diffusion tensor imaging (DTI). Eleven patients (2 males, mean age 18.8±3.9years) with a diagnosis of relapsing and remitting POMS (mean age at disease onset 13.8±2.9years, mean duration 5.1±1.9years) and healthy controls (8 males, mean age 26.4±6.5years) were recruited and imaged at 3T. A 90-gradient set Cube and Sphere acquisition and a novel DCI model known as DIstribution of Anisotropic MicrOstructural eNvironments with Diffusion-weighted imaging (DIAMOND) were used to calculate a single anisotropic compartment, an isotropic compartment, and a free diffusion compartment. Lesions and contralateral normal-appearing white matter (NAWM) in patients and whole brain WM for controls were labeled. Eleven patients and 11 controls were recruited. When comparing lesions and contralateral NAWM in patients using DCI, compartmental axial diffusivity, radial diffusivity (cRD), and mean diffusivity (cMD) were higher in lesions. Conversely, compartmental fractional anisotropy (cFA) and heterogeneity index were lower in lesions. An analysis of DTI equivalents showed the same trends. In whole-brain NAWM of patients compared to controls, cRD and cMD were higher and cFA was lower in patients. Lesions in POMS can be accurately characterized by a DCI model. Incipient changes in NAWM seen in DCI may not be readily observable by DTI.

Diagnose and treat paediatric-onset multiple sclerosis promptly to delay physical worsening and cognitive decline

Diagnose and treat paediatric-onset multiple sclerosis promptly to delay physical worsening and cognitive decline