Epstein-Barr Virus Strongly Associates With Pediatric Multiple Sclerosis, But Not Myelin Oligodendrocyte Glycoprotein-Antibody-Associated Disease.

Reported rates of Epstein-Barr virus (EBV) seropositivity in children meeting multiple sclerosis (MS) diagnostic criteria are considerably lower than those reported in adult-onset MS, putting in question a requisite role for EBV in MS development. As prior work preceded recognition of myelin oligodendrocyte glycoprotein-associated disease (MOGAD), we assessed viral serologies in 251 children with incident demyelination and prospectively ascertained diagnoses. When MOGAD was serologically accounted for, the prevalence of EBV infection among MS children exceeded 90%, whereas remote EBV infection was not associated with MOGAD risk. Together, these findings substantiate EBV's role across the MS spectrum, and support distinct pathobiological mechanisms in MS versus MOGAD. ANN NEUROL 2024;95:700-705.

Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset.

OBJECTIVE: The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. METHODS: A multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences. RESULTS: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q < 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p < 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding. INTERPRETATION: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset.

A cross-sectional study of MRI features and the gut microbiome in pediatric-onset multiple sclerosis.

OBJECTIVE: To identify gut microbiome features associated with MRI lesion burden in persons with pediatric-onset multiple sclerosis (symptom onset <18 years). METHODS: A cross-sectional study involving the Canadian Paediatric Demyelinating Disease Network study participants. Gut microbiome features (alpha diversity, phylum- and genus-level taxa) were derived using 16S rRNA sequencing from stool samples. T1- and T2-weighted lesion volumes were measured on brain MRI obtained within 6 months of stool sample procurement. Associations between the gut microbiota and MRI metrics (cube-root-transformed) were assessed using standard and Lasso regression models. RESULTS: Thirty-four participants were included; mean ages at symptom onset and MRI were 15.1 and 19.0 years, respectively, and 79% were female. The T1- and T2-weighted lesion volumes were not significantly associated with alpha diversity (age and sex-adjusted p > 0.08). At the phylum level, high Tenericutes (relative abundance) was associated with higher T1 and T2 volumes (ß coefficient = 0.25, 0.37) and high Firmicutes, Patescibacteria or Actinobacteria with lower lesion volumes (ß coefficient = -0.30 to -0.07). At the genus level, high Ruminiclostridium, whereas low Coprococcus 3 and low Erysipelatoclostridium were associated with higher lesion volumes. INTERPRETATION: Our study characterized the gut microbiota features associated with MRI lesion burden in pediatric-onset MS, shedding light onto possible pathophysiological mechanisms.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

BACKGROUND AND OBJECTIVES: Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. METHODS: We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. RESULTS: We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. DISCUSSION: The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

Addressing Health-Related Quality of Life Among Children With Multiple Sclerosis.

BACKGROUND: Children with the chronic disease multiple sclerosis (MS) report lower health-related quality of life (HRQOL) compared with children who experience transient illness. The relationship between an MS diagnosis and the HRQOL of affected children is mediated by parental HRQOL. Interventions to improve the HRQOL of children with MS should, therefore, include parents of affected children. METHODS: We performed a configurative review for improvements in the HRQOL of children facing diseases similar to MS and their parents. We used the generated concepts to form theories. Next, we performed qualitative interviews with clinicians who care for children with MS to characterize overlap between the proposed theories and usual care. Finally, we generated recommendations for improving the HRQOL of children with MS and their parents. RESULTS: We theorize that the HRQOL of children with MS and their parents may be improved by strengthening self-concept, hope, and knowledge. Qualitative interviews with 7 clinicians who care for children with MS revealed no common psychosocial care protocol. The interviews did, however, reveal sources of psychosocial care that overlap with the proposed theories and barriers to optimizing such care. CONCLUSIONS: Grounded in theory and clinically oriented practice, recommendations to improve the HRQOL of children with MS and their parents are to implement standardized screening, pool provider counseling strategies, create computer applications with psychosocial interventions, promote age-appropriate education resources, and secure positions for MS specialists.

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.

Physical and Mental Health-Related Quality of Life Trajectories Among People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Most studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) have been cross-sectional. The few longitudinal studies have not accounted for potential heterogeneity in HRQOL trajectories. There may be groups of individuals with common physical and mental HRQoL trajectories over time. Identification of early risk factors for membership in trajectories with poor HRQoL would inform on those at risk. We aimed to identify physical and mental HRQoL trajectories among people with MS and early risk factors for membership in the trajectory groups with the worst HRQoL. METHODS: Between 2004 and 2020, we queried NARCOMS participants regarding HRQoL using the RAND-12, demographics, fatigue, and physical impairments (using Patient Determined Disease Steps). We included participants who were enrolled in the NARCOMS registry within three years of MS diagnosis, lived in the United States, reported physician-confirmed MS, and had ≥3 HRQoL observations. We used group-based trajectory modelling to determine whether there were distinct clusters of individuals who followed similar HRQoL trajectories over time. We evaluated whether baseline participant characteristics associated with the probability of trajectory group membership using a multinomial logit model. RESULTS: We included 4,888 participants who completed 57,564 HRQoL questionnaires between one and 27 years after MS diagnosis. Participants had a mean (SD) age of 41.7 (9.5) years at diagnosis, and 3,978 participants (81%) were women. We identified five distinct physical HRQoL trajectories and four distinct mental HRQoL trajectories. Older age at diagnosis, worse physical impairments, and worse fatigue were associated with increased odds of being in the group with the worst physical HRQoL when compared to the four other groups. Income ≤$50,000 and no post-secondary education were associated with increased odds of membership in the group with the lowest mental HRQoL when compared to the other three groups. DISCUSSION: We identified groups of people with MS who reported similar physical and mental HRQoL trajectories over time. There are early risk factors for membership in the groups with the worst HRQoL that are easily identifiable by clinicians, providing an opportunity for early interventions.

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). OBJECTIVE: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. METHODS: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4-9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. RESULTS: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9-15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. CONCLUSION: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

The metabolic potential of the paediatric-onset multiple sclerosis gut microbiome.

BACKGROUND: The aim of this study was to examine the gut microbiome's metabolic potential in paediatric-onset MS patients (symptom onset <18 years). METHODS: We included 17 MS participants and 20 controls similar for sex, age, race, and stool consistency from the Canadian Paediatric Demyelinating Disease Network study. Stool-derived gut metagenome gene abundances were used to estimate relative abundances and turnover scores of individual microbial metabolites and the composition and diversity of carbohydrate-active enzymes (CAZymes). MS participants and controls were compared using the Wilcoxon rank-sum test, as were the disease-modifying drug (DMD) exposed and naïve MS participants. RESULTS: The median age(s) at MS symptom onset=16.1 years (interquartile range [IQR]=1.7), and at stool sample procurement=16.9/15.8 years (IQR=2.0/1.4), for the MS participants/controls. Most MS and control participants were girls (80-82%). Five (29%) of the MS participants had never been exposed to a DMD pre-stool sample and 12 (71%) had (7 to beta-interferon and 5 glatiramer acetate). While the relative abundance of metabolites did not differ between MS participants and controls, turnover scores did. MS participants had a greater potential to metabolize lipopolysaccharides than controls (score difference=1.6E-04, p = 0.034) but lower potential to metabolize peptidoglycan molecules and starch (score differences<2.2E-02, p<0.040). Further, although CAZymes diversity did not differ (p>0.050), starch-degrading subfamilies were underrepresented in MS participants versus controls (relative abundance differences >-0.34, p<0.040) and in the DMD exposed verses DMD naïve MS participants (relative abundance differences>-0.20, p<0.049). CONCLUSION: Paediatric-onset MS participants had an altered gut microbiome-related metabolic potential compared to controls, including higher breakdown of lipopolysaccharide molecules, but lower resistant starch metabolism.

Physical Activity and Sedentary Behavior Patterns Across Weekdays and Weekend Days in Youth With Multiple Sclerosis and Controls.

Background: This study quantified and compared weekday and weekend patterns of device-measured physical activity (PA) and sedentary behavior between youth with pediatric multiple sclerosis (MS) and controls for the purpose of informing future PA behavior change interventions. Methods: Participant data were obtained from 3 ongoing observational studies, and the sample included 40 participants with pediatric MS and 41 controls. Light PA (LPA), moderate to vigorous PA (MVPA), and sedentary behavior data were collected using activity monitors (ActiGraph LLC) over 1 week. The main analysis involved a 2-way mixed factor analysis of variance with group as a between-subjects factor (pediatric MS vs control) and day as a within-subjects factor (weekday vs weekend day). Results: There was no group by day interaction from the analysis of variance for percentage of activity monitor wear time spent in LPA, MVPA, or sedentary behavior. There was no effect of group for LPA, MVPA, or sedentary behavior. There was an effect of day of week on percentage of day spent in LPA, MVPA, and sedentary behavior. Conclusions: These results suggest that youth with pediatric MS and controls were less physically active and more sedentary on weekends than on weekdays, but there were no differences between groups in PA and sedentary behavior overall or by day of the week. Physical activity interventions may be more successful by initially targeting weekend day activity.

Progressive retinal changes in pediatric multiple sclerosis.

Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks - 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL: -7.9 µm, CI=5.5, p = 0.0056; GCIPL: -8.4 µm, CI=4.4, p = 0.0002) and MS (RNFL: -16 µm, CI = 3.7, p < 10-6; GCIPL: -15 µm, CI = 2.6, p < 10-6). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL: -2.6 µm/relapse, CI = 1.4, p = 0.0003; GCIPL: -2.8 µm/relapse, CI = 0.89, p < 10-6). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 µm/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS.

Stability of the gut microbiota in persons with paediatric-onset multiple sclerosis and related demyelinating diseases.

OBJECTIVE: Examine if the gut microbiota composition changes across repeated samples in paediatric-onset multiple sclerosis (MS) or monophasic-acquired demyelinating syndromes (monoADS). METHODS: A total of 36 individuals (18 MS/18 monoADS) with ⩾2 stool samples were included. Stool sample-derived DNA was sequenced. Alpha/beta diversities and genus-level taxa were analysed. RESULTS: Mean ages at first sample procurement (MS/monoADS) = 18.0/13.8 years. Median time (months) between first/second samples = 11.2 and second/third = 10.3. Alpha/beta diversities did not differ between stool samples (p > 0.09), while one genus - Solobacterium did (p = 0.001). CONCLUSIONS: The gut microbiota composition in paediatric-onset MS and monoADS exhibited stability, suggesting that single stool sample procurement is a reasonable first approach.

The health-related quality of life of children with multiple sclerosis is mediated by the health-related quality of life of their parents.

BACKGROUND: We previously found that children with the chronic disease multiple sclerosis (MS) reported lower health-related quality of life (HRQoL) when compared to children who experienced the transient illness termed monophasic acquired demyelinating syndromes (monoADS). Parents of children with MS also reported lower HRQoL. OBJECTIVES: We evaluated whether parental HRQoL mediated the relationship between the diagnosis of MS and the HRQoL of affected children. To ascertain the effect of an MS diagnosis, we compared children with MS to those with monoADS. METHODS: Children were enrolled in a prospective multi-site Canadian study. Random effects models evaluated whether parental HRQoL mediated the relationship between the diagnosis of MS and the HRQoL of affected children, adjusting for child and family characteristics. RESULTS: 207 parent-child dyads (65 MS; 142 monoADS) completed HRQoL questionnaires. When we modeled the child's HRQoL adjusting for covariates, but not the parent's HRQoL, the diagnosis of MS associated with lower HRQoL of the child (p = 0.004). When we added parental HRQOL to the model, the association between the diagnosis of MS and the child's HRQoL diminished (p = 0.13). CONCLUSIONS: Parental HRQoL mediated the relationship between the diagnosis of MS and the HRQoL of affected children, emphasizing the importance of family-centered care.

Cognitive function in pediatric-onset relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies are identified in approximately 30-50% of youth with pediatric-onset acquired demyelinating syndromes. Little is known about the cognitive sequelae of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with onset in childhood or adolescence.Overall, adults had 41% more risk than children to relapse over the whole disease course Overall, adults had 41% more risk than children to relapse over the whole disease course OBJECTIVE: To compare cognitive performance in participants with pediatric-onset relapsing MOGAD, pediatric-onset multiple sclerosis (POMS), and age-matched healthy controls. METHODS: The Penn Computerized Neurocognitive Battery (PCNB) was administered to 12 individuals with relapsing MOGAD (age = 16.3 ± 4.8 years; 75% female; disease duration = 8.1 ± 2.7 years), 68 individuals with POMS (age = 18.3 ± 4.0 years; 72% female; disease duration = 3.8 ± 3.9 years), and 108 healthy controls (age = 17.0 ± 4.9 years; 68.5% female). Accuracy was assessed on four domains: Executive Function, Episodic Memory, Complex Cognition, Social Cognition; and overall response time (RT) and RT across three factors (i.e., Time Constrained, Open-Window, Memory). Global performance was determined by a composite score. Multiple linear regression was used to examine group differences on PCNB domain and factor z-scores, controlling for age and sex. We also covaried disease duration for relapsing MOGAD vs. POMS analyses. RESULTS: Relative to healthy controls, relapsing MOGAD participants were less accurate on the Complex Cognition domain (B=-0.28, SE=0.11, p=.02), and had slower overall response time (B=-0.16, SE=0.07, p=.02). Relative to POMS, relapsing MOGAD participants were more accurate on the Executive Function domain (B = 0.70, SE=0.30, p=.02) and on the battery overall (B = 0.41, SE=0.18, p=.02). Relative to controls, overall PCNB score was significantly lower in the POMS group (B=-0.28, SE=0.06, p<.001) whereas the relapsing MOGAD participants did not differ from controls (p=.06) on the overall PCNB score. CONCLUSIONS: The relapsing MOGAD group demonstrated reduced reasoning skills and slower overall response time, relative to controls. A broad pattern of deficits was observed among POMS participants relative to controls. Overall, cognitive difficulties in the MOGAD group were milder relative to the POMS group.

[Formula: see text] Disrupted cognitive development following pediatric acquired demyelinating syndromes: a longitudinal study.

Long-term cognitive deficits have been observed in some children who experience an acquired demyelinating syndrome (ADS). We examined changes in cognitive functioning over the first two years following incident ADS andtested whether normalized brain and thalamic volume accounted for decline over time. Twenty-five youth (mean age 12.8 years) with ADS, 9 of whom were diagnosed with multiple sclerosis (MS) and 16 of whom experienced monophasic ADS (monoADS), underwent two neuropsychological evaluationsand MRI scans at approximately6- and 24-months post ADS-onset. We examined changes in cognitive outcomes over time and between patient groups. Generalized linear mixed-effect regression models were used to examine the association of normalized brain and thalamic volumesbetween the two timepointswith cognitive z-scores. Cognitive performance was within the age-expected range for both groups and remained stable over time on 15 measures. In the combined sample of monoADS and MS patients, declines (p < .05) were noted on the Symbol Digit Modalities Test (SDMT), the Auditory Working Memory (AWM), and the WJ-III Visual Matching (VisMat)tests, but did not survive FDR correction. Clinically significant declines, as measured by the Reliable Change Index, were observed on the SDMT,AWM, and VisMattests by 19, 42, and 32%, respectively. Lower normalized brain volume at 6-months predicted a negative change in SDMT (B = 0.45, 95%CI: 0.07,0.83) and AWM (B = 0.30, 95%CI: 0.13, 0.47). Chronicity of demyelination is not required for cognitive decline nor for reduced brain volume, suggesting that even a single demyelinating event may negatively impact cognitive potential in children.

Metagenomic Analysis of the Pediatric-Onset Multiple Sclerosis Gut Microbiome.

BACKGROUND AND OBJECTIVES: Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls. METHODS: Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with MS (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha diversity, relative abundance, and prevalence using Wilcoxon rank sum, ALDEx2, and Fisher exact tests, respectively. RESULTS: Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD-naive. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or DMD status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC -0.48, p = 0.039). Differences by DMD status included lower phosphate butyryl transferase for DMD-naive vs exposed patients with MS (LFC -1.0, p = 0.033). DISCUSSION: The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

The gut microbiota in pediatric multiple sclerosis and demyelinating syndromes.

OBJECTIVE: To examine the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS). METHODS: We compared stool-derived microbiota of Canadian Pediatric Demyelinating Disease Network study participants ≤21 years old, with MS (disease-modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset <18 years), and unaffected controls. All were ≥30 days without antibiotics or corticosteroids. V4 region 16S RNA gene-derived amplicon sequence variants (Illumina MiSeq) were assessed using negative binomial regression and network analyses; rate ratios were age- and sex-adjusted (aRR). RESULTS: Thirty-two MS, 41 monoADS (symptom onset [mean] = 14.0 and 6.9 years) and 36 control participants were included; 75%/56%/58% were female, with mean ages at stool sample = 16.5/13.8/15.1 years, respectively. Nine MS cases (28%) were DMD-naïve. Although microbiota diversity (alpha, beta) did not differ between participants (p > 0.1), taxa-level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6-11.2, p = 0.004, Q = 0.01), and lower abundances of short-chain fatty acid (SCFA)-producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q < 0.05). DMD-naïve MS cases were depleted for Clostridiales vadin-BB60 (unnamed species) versus either DMD-exposed, controls (p, Q < 0.01), or monoADS (p = 0.001, Q = 0.06) and exhibited altered community connectedness (p < 10-9 Kruskal-Wallis), with SCFA-producing taxa underrepresented. Consistent taxa-level findings from an independent US Network of Pediatric MS Centers case/control (n = 51/42) cohort included >eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8-12.8, p < 0.05) in MS cases and 72%-80% lower abundance of SCFA-producing Ruminococcaceae-NK4A214 (aRR = 0.38-0.2, p ≤ 0.01). INTERPRETATION: Gut microbiota community structure, function and connectivity, and not just individual taxa, are of likely importance in MS.

Comparison of Spinal Cord Magnetic Resonance Imaging Features Among Children With Acquired Demyelinating Syndromes.

Importance: The recognition of magnetic resonance imaging (MRI) features associated with distinct causes of myelitis in children is essential to guide investigations and support diagnostic categorization. Objective: To determine the clinical and MRI features and outcomes associated with spinal cord involvement in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), multiple sclerosis (MS), and seronegative monophasic myelitis. Design, Setting, and Participants: In this cohort study, participants were recruited between 2004 and 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study, which enrolled youth younger than 18 years presenting within 90 days of an acquired demyelinating syndrome. Of the 430 participants recruited, those with lesions on available spine MRI and anti-MOG testing performed on archived samples obtained close to clinical presentation were selected. Participants with poor-quality images and final diagnoses of nondemyelinating disease, anti-aquaporin 4 antibody positivity, and relapsing seronegative myelitis were excluded. Data analysis was performed from December 2019 to November 2020. Main Outcomes and Measures: Spinal cord involvement was evaluated on 324 MRI sequences, with reviewers blinded to clinical, serological, and brain MRI findings. Associated clinical features and disability scores at 5 years of follow-up were retrieved. Results were compared between groups. Results: A total of 107 participants (median [IQR] age at onset, 11.14 [5.59-13.39] years; 55 girls [51%]) were included in the analyses; 40 children had MOGAD, 21 had MS, and 46 had seronegative myelitis. Longitudinally extensive lesions were very common among children with MOGAD (30 of 40 children [75%]), less common among those with seronegative myelitis (20 of 46 children [43%]), and rare in children with MS (1 of 21 children [5%]). Axial gray matter T2-hyperintensity (ie, the H-sign) was observed in 22 of 35 children (63%) with MOGAD, in 14 of 42 children (33%) with seronegative myelitis, and in none of those with MS. The presence of leptomeningeal enhancement was highly suggestive for MOGAD (22 of 32 children [69%] with MOGAD vs 10 of 38 children [26%] with seronegative myelitis and 1 of 15 children [7%] with MS). Children with MOGAD were more likely to have complete lesion resolution on serial images (14 of 21 children [67%]) compared with those with MS (0 of 13 children). Conclusions and Relevance: These findings suggest that several features may help identify children at presentation who are more likely to have myelitis associated with MOGAD. Prominent involvement of gray matter and leptomeningeal enhancement are common in pediatric MOGAD, although the pathological underpinning of these observations requires further study.

Memory, processing of emotional stimuli, and volume of limbic structures in pediatric-onset multiple sclerosis.

OBJECTIVE: The limbic system is involved in memory and in processing of emotional stimuli. We measured volume of the hippocampus, amygdala, and thalamus, and assessed their relative contribution to episodic memory and emotion identification in POMS. METHOD: Sixty-five POMS participants (Mage = 18.3 ± 3.9 years; 48 female (73.8%)), average disease duration = 3.8 ± 3.8 years) and 76 age- and sex-matched controls (Mage = 18.1 ± 4.6 years; 49 female (64.5%)) completed the Penn Computerized Neurocognitive Battery (PCNB); 59 of 65 POMS participants and 69 out of 76 controls underwent 3 T MRI scanning. We derived age-adjusted Z-scores on accuracy and response time (RT) measures of episodic memory and emotion identification of the PCNB. Magnetic resonance imaging (MRI) volumetrics were normalized using the scaling factor computed by SIENAx. On PCNB tests that differed between groups, we used multiple linear regression to assess relationships between regional brain volumes and either episodic memory or emotion identification outcomes controlling for age, sex, accuracy/RT, and parental education. RESULTS: POMS participants were slower and less accurate than controls on the episodic memory domain but did not differ from controls on emotion outcomes. At the subtest level, POMS participants showed reduced accuracy on Word Memory (p = .002) and slower performance on Face Memory (p = .04) subtests. POMS participants had smaller total and regional brain volumes of the hippocampus, amygdala, and thalamus (p values ≤ 0.01). Collapsing across groups, both hippocampal and thalamic volume were significant predictors of Word Memory accuracy; hippocampal volume (B = 0.24, SE = 0.10, p = .02) was more strongly associated with Word Memory performance than thalamic volume (B = 0.16, SE = 0.05, p = .003), though the estimate with was less precise. CONCLUSIONS: POMS participants showed reduced episodic memory performance compared to controls. Aspects of episodic memory performance were associated with hippocampal and thalamic volume. Emotion identification was intact, despite volume loss in the amygdala.

Examining cognitive speed and accuracy dysfunction in youth and young adults with pediatric-onset multiple sclerosis using a computerized neurocognitive battery.

OBJECTIVE: We evaluated performance on the Penn Computerized Neurocognitive Battery (PCNB), a tool assessing accuracy and response time across four cognitive domains, alongside the Symbol Digit Modalities Test (SDMT), a measure of processing speed commonly used in MS. We determined whether performance decrements are more likely to be detected on measures of accuracy versus response time in pediatric-onset multiple sclerosis (POMS). METHODS: Performance on the SDMT, accuracy on PCNB tests belonging to four domains (executive function, episodic memory, complex cognition, social cognition), and response time on the PCNB were compared for 65 POMS patients (age range: 8-29 years) and 76 healthy controls (HCs) by ANCOVA. Associations between the Overall PCNB score and SDMT were examined for both groups, and their agreement in classifying impairment was assessed using Cohen's kappa. RESULTS: POMS patients (age at testing = 18.3 ± 4.0 years; age at POMS onset = 14.9 ± 2.3 years) demonstrated reduced accuracy relative to HCs on tests of working memory, attention/inhibition, verbal memory, and visuospatial processing, after adjusting for response time (p ≤ .002). Patients demonstrated slower overall response time on the PCNB (p = .003), while group differences on the SDMT did not meet significance (p = .03). Performance on the PCNB and SDMT were correlated (MS: r = 0.43, HC: r = 0.50, both p < .001), however, the degree of agreement for impairment was minimal (k = 0.22, p = .14). CONCLUSION: Specific cognitive deficits exist independently of slowed information processing speed in POMS, and may represent more significant areas of dysfunction. Delineation of accuracy and response time in neuropsychological assessment is important to identify areas of cognitive deficit in POMS. (PsycInfo Database Record (c) 2021 APA, all rights reserved).