Faculty Bibliography

BACKGROUND/UNASSIGNED:Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. OBJECTIVE/UNASSIGNED:To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. METHODS/UNASSIGNED:AEs)/100 patient-years were analysed by on-study nadir ALC. RESULTS/UNASSIGNED:/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. CONCLUSION/UNASSIGNED:In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

OBJECTIVE:To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness. METHODS:From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records. RESULTS:We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders). Thirty-seven underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome. CONCLUSIONS:Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at-risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample.

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

Walking impairments are a debilitating feature of multiple sclerosis (MS) because of the direct interference with daily activity. The management of motor symptoms in those with MS remains a therapeutic challenge. Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation that is emerging as a promising rehabilitative tool but requires further characterization to determine its optimal therapeutic use. In this randomized, sham-controlled proof-of-concept study, we tested the immediate effects of a single tDCS session on walking and functional mobility in those with MS. Seventeen participants with MS completed one 20-min session of aerobic exercise, randomly assigned to be paired with either active (2.5 mA, n = 9) or sham (n = 8) tDCS over the primary motor cortex (M1). The groups (active vs. sham) were matched according to gender (50% vs. 60% F), age (52.1 ± 12.85 vs. 54.2 ± 8.5 years), and level of neurological disability (median Expanded Disability Status Scale score 5.5 vs. 5). Gait speed on the 10-m walk test and the Timed Up and Go (TUG) time were measured by a wearable inertial sensor immediately before and following the 20-min session, with changes compared between conditions and time. There were no significant differences in gait speed or TUG time changes following the session in the full sample or between the active vs. sham groups. These findings suggest that a single session of anodal tDCS over M1 is not sufficient to affect walking and functional mobility in those with MS. Instead, behavioral motor response of tDCS is likely to be cumulative, and the effects of multiple tDCS sessions require further study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03658668.

OBJECTIVE:To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric MS and clinically isolated syndrome (CIS). METHODS:This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PS) were computed including pre-identified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2 hyperintense and gadolinium-enhancing lesions on MRI brain were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS:741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs. injectable 14.4 years, p=0.001) and less likely to have a monofocal presentation. In PS-quintile adjusted analysis, those on newer DMTs had lower relapse rate than those on injectables (rate ratio 0.45, 95%CI 0.29-0.70, p<0.001; rate difference 0.27, 0.14-0.40, p=0.004). One would need to treat with newer over injectable DMTs for 3.7 person-years to prevent one relapse. Those started on newer DMTs had lower rate of new/enlarging T2 (HR 0.51, 0.36-0.72, p<0.001) and gadolinium-enhancing lesions (HR 0.38, 0.23-0.63, p<0.001) than those on injectables. INTERPRETATION/CONCLUSIONS:Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. This article is protected by copyright. All rights reserved.

OBJECTIVE:demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study. METHODS:Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA). RESULTS:Of the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group. CONCLUSION/CONCLUSIONS:Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

Pediatric multiple sclerosis (MS) is an increasingly recognized rare subgroup of patients presenting with a unique set of diagnostic challenges. Understanding the early development of MS may offer a window into the pathogenesis of disease; however further research is needed, particularly within the field of genetics and to understand the complex environmental and biological interactions at work. Acute disseminated encephalomyelitis (ADEM) remains a hallmark presentation of early pediatric disease and can be a monophasic illness or end up being reclassified as a relapsing disorder. The clinical expression is shaped in part by the prepubertal or postpubertal state of the patient. Other syndromes can also present with ADEM, and a specific differential diagnosis exists for children presenting with any initial demyelinating event (IDE). New definitions and criteria have allowed early detection of MS. However applying adult criteria to very young children should be approached with caution. There is now a major effort in studying disease-modifying therapy (DMT) in children due to requirements from regulatory authorities. Pediatric patients respond well to therapy and often do best with an interdisciplinary approach focusing on social aspects, cognition, and fatigue which enhances the achievement of successful outcomes.
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