Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children.

Importance: Obesity reportedly increases the risk of pediatric multiple sclerosis (MS), but little is known about its association with disease course. Objective: To investigate the association of obesity with pediatric MS risk and with first-line therapy response among children with MS. Design, Setting, and Participants: This single-center retrospective study used the medical records and database at the Center for MS in Childhood and Adolescence, Göttingen, Germany. The study included 453 patients with relapsing-remitting pediatric MS and body mass index (BMI) measurement taken within 6 months of diagnosis. Onset of the disease occurred between April 28, 1990, and June 26, 2016, and the mean disease duration was 38.4 months. Data were collected from July 14, 2016, to December 18, 2017. Main Outcomes and Measures: Data on BMIs were stratified by sex and age using German BMI references and compared with the BMI data of 14 747 controls from a nationwide child health survey for odds ratio (OR) estimates. Baseline magnetic resonance imaging findings, intervals between first and second MS attacks, annualized relapse rates before and during treatment with interferon beta-1a or -1b and glatiramer acetate, frequency of second-line treatment, and Expanded Disability Status Scale (EDSS) scores were compared between nonoverweight (BMI≤90th percentile), overweight (BMI>90th-97th percentile), and obese (BMI>97th percentile) patients. Results: In total, 453 patients with pediatric MS were included, of whom 306 (67.5%) were female, and the mean (SD) age at diagnosis was 13.7 (2.7) years. At diagnosis, 126 patients (27.8%) were overweight or obese, with obesity associated with statistically significant twofold odds of MS in both sexes (girls OR, 2.19; 95% CI, 1.5-3.1; P < .001 vs boys OR, 2.14; 95% CI, 1.3-3.5; P = .003). Obese patients, compared with nonoverweight patients, had statistically significantly more relapses on first-line treatment with interferon beta and glatiramer acetate (ARR, 1.29 vs 0.72; P < .001) and a higher rate of second-line treatment (21 [56.8%] of 37 vs 48 [38.7%] of 124; P = .06). Baseline neuroimaging, interval between first and second MS attacks, pretreatment relapses, and EDSS progression scores were not correlated with BMI. Conclusions and Relevance: In this study, increased pediatric MS risk appeared to be associated with obesity, and obese patients did not respond well to first-line medications; altered pharmacokinetics appeared to be most likely factors in treatment response, suggesting that achieving healthy weight or adjusting the dose according to BMI could improve therapy response.

Therapy of highly active pediatric multiple sclerosis.

OBJECTIVE: Study aims were to determine the frequency of highly active disease in pediatric multiple sclerosis (MS), the response to natalizumab (NTZ) and fingolimod (FTY) treatment, and the impact of current treatment modalities on the clinical course. METHODS: Retrospective single-center study in the German Center for MS in Childhood and Adolescence. RESULTS: Of 144 patients with first MS manifestation between 2011 and 2015, 41.6% fulfilled the criteria for highly active MS. In total, 55 patients treated with NTZ and 23 with FTY demonstrated a significant reduction in relapse rate (NTZ: 95.2%, FTY: 75%), new T2 lesions (NTZ: 97%, FTY: 81%), and contrast-enhancing lesions (NTZ: 97%, FTY: 93%). However, seven patients switched from NTZ to FTY experienced an increase in disease activity. Comparing pediatric MS patients treated in 2005 with those treated in 2015 showed a 46% reduction in relapse rate and a 44% reduction in mean Expanded Disability Status Scale (EDSS). CONCLUSION: The rate of highly active disease among pediatric MS patients is high; more than 40% in our cohort. Response to NTZ and FTY treatment is similar if not better than observed in adults. Current treatment modalities including earlier treatment initiation and the introduction of NTZ and FTY have significantly improved the clinical course of pediatric MS.

Interferon beta-1b in treatment-naïve paediatric patients with relapsing-remitting multiple sclerosis: Two-year results from the BETAPAEDIC study.

BACKGROUND AND OBJECTIVE: Study evaluating Betaferon(R)'s safety and tolerability in paediatric patients with multiple sclerosis (BETAPAEDIC) is a prospective, open-label observational multicentre study to assess the safety and effectiveness of interferon beta-1b in paediatric patients with relapsing-remitting multiple sclerosis. METHODS: Treatment-naïve patients (12-16 years) scheduled to start interferon beta-1b were enrolled with follow-up visits every six months for two years. Effectiveness was evaluated by annualised relapse rate, Expanded Disability Status Scale progression, cranial magnetic resonance imaging and cognitive testing. Fatigue was assessed by the Fatigue Severity Scale. RESULTS: Sixty-eight patients were screened and 67 enrolled, with mean (standard deviation) age 14.2 (1.3) years (n=65 in the effectiveness analysis). Mean disease duration was 11 months before study enrolment; at baseline, mean (standard deviation) Expanded Disability Status Scale was 0.6 (1.0); T2 lesion number 18.3 (15.1). Mean annualised relapse rate during the study was 0.7 (n=57), 28/57 patients (49.1%) had no relapses and for 40/52 (76.9%) no Expanded Disability Status Scale progression was observed; 23/56 (41.1%) were relapse- and progression-free to last follow-up. Neuropsychological test and fatigue scores were within normal ranges (baseline and last follow-up). Eighteen patients had fatigue at some point. New T2 and gadolinium-enhancing (Gd+) lesions were seen in 43/55 (66.2%) and 29/55 (52.7%) patients respectively. Most frequent adverse events were influenza-like illness, headache, injection-site reactions and elevated liver enzymes. CONCLUSION: Interferon beta-1b is an effective treatment with a favourable safety profile for paediatric patients.

MRI-based diagnostic biomarkers for early onset pediatric multiple sclerosis.

Currently, it is unclear whether pediatric multiple sclerosis (PMS) is a pathoetiologically homogeneous disease phenotype due to clinical and epidemiological differences between early and late onset PMS (EOPMS and LOPMS). Consequently, the question was raised whether diagnostic guidelines need to be complemented by specific EOPMS markers. To search for such markers, we analyzed cerebral MRI images acquired with standard protocols using computer-based classification techniques. Specifically, we applied classification algorithms to gray (GM) and white matter (WM) tissue probability parameters of small brain regions derived from T2-weighted MRI images of EOPMS patients (onset <12 years), LOPMS patients (onset ≥12 years), and healthy controls (HC). This was done for PMS subgroups matched for disease duration and participant age independently. As expected, maximal diagnostic information for distinguishing PMS patients and HC was found in a periventricular WM area containing lesions (87.1% accuracy, p < 2.2 × 10(-5)). MRI-based biomarkers specific for EOPMS were identified in prefrontal cortex. Specifically, a coordinate in middle frontal gyrus contained maximal diagnostic information (77.3%, p = 1.8 × 10(-4)). Taken together, we were able to identify biomarkers reflecting pathognomonic processes specific for MS patients with very early onset. Especially GM involvement in the separation between PMS subgroups suggests that conventional MRI contains a richer set of diagnostically informative features than previously assumed.

Pediatric onset multiple sclerosis: McDonald criteria 2010 and the contribution of spinal cord MRI.

BACKGROUND: Diagnostic magnetic resonance imaging (MRI) criteria have not been sufficiently validated in pediatric multiple sclerosis (MS) despite differences in epidemiologic data and clinical disease courses between pediatric and adult MS. OBJECTIVE: The objective of this paper is to evaluate the diagnostic applicability and validity of the revised McDonald diagnostic criteria 2010 in a large cohort of pediatric-onset MS patients (POMS) and compare them to previously recommended MRI-based classifications. Furthermore, we aimed to investigate the contribution of spinal cord lesions to the revised McDonald criteria 2010. METHODS: A cohort of 85 patients with definite MS, age at onset 2.8-18 years, was analyzed in a retrospective multicenter study. Number and regional distribution of T2w and contrast-enhancing T1w lesions at initial and follow-up MRIs were main outcome measures. RESULTS: In 62% of POMS the initial MRI within four weeks after symptom onset was sufficient to diagnose MS according to the revised McDonald criteria 2010. In a subcohort of patients with spinal MRI at first presentation, 10% reached the dissemination in space (DIS) and dissemination in time (DIT) criteria only by the inclusion of contrast-enhancing spinal lesions. CONCLUSIONS: The revised McDonald criteria 2010 facilitate the diagnosis of POMS already at first presentation. The addition of a spinal cord MRI was helpful only in selected cases.