Faculty Bibliography

ADEM is an inflammatory disease, with new onset polyfocal neurologic symptoms, encephalopathy and multifocal demyelination, typically in childhood. Initial diagnosis of ADEM is challenging and up to 20 % of children with MS or NMOSD are initially diagnosed with ADEM. We describe characteristics of patients with monophasic ADEM vs. recurrent demyelinating syndromes at onset and identify features consistent with monophasic course. This is a multicenter observational study of children with demyelinating disease, followed at 12 regional pediatric MS centers. Descriptive statistics were used to report patient characteristics, clinical/imaging features and outcomes. Logistic regression was used to predict features associated with monophasic course. As of July 2019, 837 children with final diagnosis of ADEM (n = 79), MS (n = 646) or NMOSD (n = 112) were identified. The mean follow-up was 5·7 +/- 3·2 years. ADEM patients were youngest with mean age at first event 5·2 +/- 3·8 years (p < 0.001) and male predominant (66 %) (p < 0·001). After 2 years of follow-up, 83 % of patients initially diagnosed with monophasic ADEM retained this diagnosis. In multivariable analysis, older age (OR 1·16 [95 % CI 1·02 "“ 1·33] for 1-year increase, p = 0·02), presenting with optic neuritis (OR 8.18 [95 % CI 1.88 "“ 35.64], p = 0·005) and presence of gadolinium enhancement (OR 4.08 [95 % CI 1.38 "“ 12.08], p = 0·011) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Children with monophasic ADEM vs. those reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at onset.

OBJECTIVE/UNASSIGNED:Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS/UNASSIGNED:Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS/UNASSIGNED: < 0.001). CONCLUSION/UNASSIGNED:Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

OBJECTIVE:To identify features of the gut microbiome associated with multiple sclerosis activity over time. METHODS:We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric-onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice-Williams-Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium-enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease-modifying therapies. RESULTS:Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co-occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium-enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. INTERPRETATION/CONCLUSIONS:Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity.

Background: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating central nervous system (CNS) disorder, characterized by new onset polyfocal neurologic symptoms with encephalopathy and multifocal demyelination, typically occurring in early childhood. The initial diagnosis of ADEM can be challenging as up to 20% of children with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) are initially diagnosed with ADEM.
Objective(s): To describe characteristics of patients with ADEM vs. recurrent demyelinating syndromes (MS or NMOSD) at the time of initial presentation and identify features at disease onset associated with monophasic demyelinating disease.
Method(s): This is a multicenter observational cohort study of children with a demyelinating disease diagnosis of ADEM, multiphasic ADEM, MS, and NMOSD who were followed at 12 regional pediatric MS referral centers in the US Network of Pediatric MS Centers. Descriptive statistics were used to report patient characteristics, clinical/imaging presenting features and clinical followup outcomes. Logistic regression was used to predict features associated with monophasic demyelination and to identify features associated with poor recovery from ADEM in patients with ADEM-like presentation at 2 years from disease onset.
Result(s): As of July 2019, 872 pediatric patients with a final diagnosis of ADEM (n=89), MS (n= 664) and NMOSD (n=119) were identified. The mean follow-up for all patients was 5.7 +/-3.1 years. ADEM patients were the youngest with mean age at first event 5.4 +/-3.7 years and male predominance (62%), p < 0.001. Severe clinical symptoms at onset were more frequent in ADEM (55% vs. 35% NMOSD and 15% MS, p < 0.001). After 2 years of follow-up, 86.2% of patients initially diagnosed with ADEM retained this diagnosis (ADEM to ADEM), while 10.1% were later reclassified as MS and 3.6% with NMOSD. In univariable regression, younger age at first event and having an antecedent infection at onset were associated with ADEM, while presentation with optic neuritis and gadolinium enhancement on brain MRI were associated with ADEM reclassification to MS or NMOSD after 2 years of follow up. In a multivariable analysis, older age at first event (OR 1.29 [95% CI 1.07-1.56], p = 0.007), presenting with optic neuritis (OR 27.56 [95% CI 3.19-238.14], p = 0.003) and presence of gadolinium enhancement on brain MRI at onset (OR 14.36 [95% CI 2.53-81.36], p = 0.003) were associated with reclassification of ADEM to MS or NMOSD within 2 years. Younger age at onset was associated with higher risk of EDSS 2.0 or higher after 2 years of follow-up (p = 0.0422).
Conclusion(s): Those who remain classified as ADEM vs. those who are reclassified as other demyelinating disorders are younger at onset, more likely to be male, have a more severe initial presentation, and are less likely to have optic neuritis or gadolinium enhancing lesions at onset

OBJECTIVE:To characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS). METHODS:This was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005. RESULTS:In total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score. CONCLUSIONS:Persons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis.

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.

BACKGROUND/UNASSIGNED:Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE/UNASSIGNED:To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS/UNASSIGNED:Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS/UNASSIGNED: = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION/UNASSIGNED:Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.