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.

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.

Silent New Brain MRI Lesions in Children with MOG-Antibody Associated Disease.

Anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and clinical importance of acquired asymptomatic brain magnetic resonance imaging (MRI) lesions in a prospective incident cohort of 74 MOG-IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG-IgG positive participants, most commonly within the first months post-onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy. ANN NEUROL 2021;89:408-413.

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.

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.

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.

Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis.

BACKGROUND: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. OBJECTIVES: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. METHODS: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. RESULTS: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. CONCLUSIONS: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis.

OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.

Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis.

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8+CD161highTCR-Vα7.2+ MAIT T cells and CD4+CCR2+CCR5+ Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4+CD25hiCD127lowFOXP3+ Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.

Pediatric-onset multiple sclerosis is associated with reduced parental health-related quality of life and family functioning.

BACKGROUND: Diagnosis of multiple sclerosis (MS) during childhood has the potential to impact the affected child's self-perception and the health-related quality of life (HRQoL) of the family. OBJECTIVE: To evaluate the impact of chronic disease, in children ascertained as having MS and their families, when compared to those with monophasic acquired demyelinating syndrome (monoADS). METHODS: In a national prospective cohort study of pediatric acquired demyelinating syndromes (ADS), the HRQoL of children and their families was captured using the Pediatric Quality of Life Inventory (PedsQL™) Modules. RESULTS: Participants (58 MS; 178 monoADS) provided cross-sectional HRQoL data a median (interquartile range (IQR)) of 4.1 (2.0-6.0) years after disease onset. The HRQoL of parents of children with MS and their family functioning was lower when compared to that of parents and families of children with monoADS (both p < 0.001); parents of children with MS reported greater emotional dysfunction, worry, worse communication, and lower family functioning irrespective of clinical disease activity. Self-reports of the MS and monoADS participants did not suggest a difference in overall HRQoL or fatigue after adjusting for age of the child at the time of assessment. CONCLUSION: While children with MS did not self-report lower HRQoL compared to children who experienced monoADS, the diagnosis of MS during childhood was negatively associated with parental HRQoL and family functioning.

The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk.

BACKGROUND: Pediatric acquired demyelinating syndromes (ADSs) are monophasic (mono-ADS) in 70% of cases and represent the first attack of multiple sclerosis (MS) in 30%. Secondhand tobacco smoke (SHS) exposure has been implicated as a risk factor for adult-onset MS. Little is known about whether SHS presents an additive risk beyond genetic factors and other environmental exposures associated with pediatric MS. METHODS: This study examined SHS exposure in 216 children with mono-ADS and 81 children with MS. Interactions between SHS, HLA-DRB1*15 alleles, serum 25-hydroxyvitamin D concentrations, and serological evidence of remote Epstein-Barr virus (EBV) exposure were evaluated. RESULTS: SHS exposure was more common in children with MS (37% exposed) compared to mono-ADS (29.5% exposed). Compared to mono-ADS, SHS exposure was not an independent risk factor for MS. When both SHS exposure and HLA-DRB1*15 were present, the odds for MS increased (odds ratio (OR) = 3.7; 95% confidence interval (CI): 1.17-11.9) compared to mono-ADS. Interactions between SHS and vitamin D or EBV did not associate with MS. CONCLUSION: Exposure to SHS is a risk factor for central nervous system (CNS) demyelination. Results suggest that SHS exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with mono-ADS.

Detection and clinical correlation of leukocortical lesions in pediatric-onset multiple sclerosis on multi-contrast MRI.

OBJECTIVE: To determine the frequency of cortical lesions (CLs) in patients with pediatric-onset multiple sclerosis (POMS) using multi-contrast magnetic resonance imaging (MRI), and the relationship between frontal CL load and upper limb dexterity assessed with the Nine-Hole Peg Test (9-HPT). METHODS: Participants completed the 9-HPT and were imaged on a 3T MRI scanner to collect T1-weighted three-dimensional (3D) magnetization prepared rapid gradient echo (MPRAGE), proton density-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. CLs were manually segmented using all MRI contrasts. RESULTS: We enrolled 24 participants with POMS (mean (standard deviation) age at first symptom: 13.3 (±2.7) years; mean age at scan: 18.8 (±3) years; mean disease duration of 5 (±3.2) years). A total of 391 CLs (mean, 16.3 ± 27.2; median, 7) were identified in 19 of 24 POMS patients (79%). The total number of CLs was positively associated with white matter lesion volume ( p = 0.04) but not with thalamic volume, age at the time of the scan, or disease duration. The number of frontal CLs was associated with slower performance on the 9-HPT ( p = 0.05). CONCLUSION: Multi-contrast 3T MRI led to a high rate of CL detection, demonstrating that cortical pathology occurs even in pediatric-onset disease. Frontal lobe CL count was associated with reduced manual dexterity, indicating that these CLs are clinically relevant.

Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination.

Epstein-Barr virus (EBV) infection is associated with increased multiple sclerosis (MS) risk. Recently, cytomegalovirus (CMV) infection has been proposed as a protective factor against MS development. We determined EBV, herpes simplex virus, varicella-zoster virus and CMV seroprevalence in 247 prospectively followed children with acquired demyelinating syndromes (ADS). Remote EBV infection was more common in children with MS than those with monophasic ADS while CMV infection was more common in children with monophasic ADS. Children displaying evidence of remote EBV without CMV infection were at highest risk of subsequent MS diagnosis. Viral infection repertoire detected at ADS provides important prognostic information.

Cognitive and Behavioral Functioning in Childhood Acquired Demyelinating Syndromes.

OBJECTIVES: The aim of this study was to describe cognitive, academic, and psychosocial outcomes after an incident demyelinating event (acquired demyelinating syndromes, ADS) in childhood and to investigate the contribution of brain lesions and confirmed MS diagnosis on outcome. METHODS: Thirty-six patients with ADS (mean age=12.2 years, SD=2.7, range: 7-16 years) underwent brain MRI scans at presentation and at 6-months follow-up. T2-weighted lesions on MRI were assessed using a binary classification. At 6-months follow-up, patients underwent neuropsychological evaluation and were compared with 42 healthy controls. RESULTS: Cognitive, academic, and behavioral outcomes did not differ between the patients with ADS and controls. Three of 36 patients (8.3%) were identified with cognitive impairment, as determined by performance falling ≤1.5 SD below normative values on more than four independent tests in the battery. Poor performance on a visuomotor integration task was most common, observed among 6/32 patients, but this did not differ significantly from controls. Twelve of 36 patients received a diagnosis of MS within 3 years post-ADS. Patients with MS did not differ from children with monophasic ADS in terms of cognitive performance at the 6-months follow-up. Fatigue symptoms were reported in 50% of patients, irrespective of MS diagnosis. Presence of brain lesions at onset and 6 months post-incident demyelinating event did not associate with cognitive outcome. CONCLUSIONS: Children with ADS experience a favorable short-term neurocognitive outcome, even those confirmed to have MS. Longitudinal evaluations of children with monophasic ADS and MS are required to determine the possibility of late-emerging sequelae and their time course. (JINS, 2016, 22, 1050-1060).

Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice.

BACKGROUND: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS. OBJECTIVE: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity. METHODS: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status. RESULTS: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice. CONCLUSION: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.

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.

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.

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.

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.

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.