Neurodegeneration and humoral response proteins in cerebrospinal fluid associate with pediatric-onset multiple sclerosis and not monophasic demyelinating syndromes in childhood.

BACKGROUND: Pediatric-onset multiple sclerosis (POMS) represents the earliest stage of disease pathogenesis. Investigating the cerebrospinal fluid (CSF) proteome in POMS may provide novel insights into early MS processes. OBJECTIVE: To analyze CSF obtained from children at time of initial central nervous system (CNS) acquired demyelinating syndrome (ADS), to compare CSF proteome of those subsequently ascertained as having POMS versus monophasic acquired demyelinating syndrome (mADS). METHODS: Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry (LC-MS) was performed in a Dutch discovery cohort (POMS n = 28; mADS n = 39). Parallel reaction monitoring-mass spectrometry (PRM-MS) was performed on selected proteins more abundant in POMS in a combined Dutch and Canadian validation cohort (POMS n = 48; mADS n = 106). RESULTS: Discovery identified 5580 peptides belonging to 576 proteins; 58 proteins were differentially abundant with ⩾2 peptides between POMS and mADS, of which 28 more abundant in POMS. Fourteen had increased abundance in POMS with ⩾8 unique peptides. Five selected proteins were all confirmed within validation. Adjusted for age, 2 out of 5 proteins remained more abundant in POMS, that is, Carboxypeptidase E (CPE) and Semaphorin-7A (SEMA7A). CONCLUSION: This exploratory study identified several CSF proteins associated with POMS and not mADS, potentially reflecting neurodegeneration, compensatory neuroprotection, and humoral response in POMS. The proteins associated with POMS highly correlated with age at CSF sampling.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.

Inhibition of Bruton's Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.

Fast automatic segmentation of thalamic nuclei from MP2RAGE acquisition at 7 Tesla.

PURPOSE: Thalamic nuclei are largely invisible in conventional MRI due to poor contrast. Thalamus Optimized Multi-Atlas Segmentation (THOMAS) provides automatic segmentation of 12 thalamic nuclei using white-matter-nulled (WMn) Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence at 7T, but increases overall scan duration. Routinely acquired, bias-corrected Magnetization Prepared 2 Rapid Gradient Echo (MP2RAGE) sequence yields superior tissue contrast and quantitative T1 maps. Application of THOMAS to MP2RAGE has been investigated in this study. METHODS: Eight healthy volunteers and five pediatric-onset multiple sclerosis patients were recruited at Children's Hospital of Philadelphia and scanned at Siemens 7T with WMn-MPRAGE and multi-echo-MP2RAGE (ME-MP2RAGE) sequences. White-matter-nulled contrast was synthesized (MP2-SYN) from T1 maps from ME-MP2RAGE sequence. Thalamic nuclei were segmented using THOMAS joint label fusion algorithm from WMn-MPRAGE and MP2-SYN datasets. THOMAS pipeline was modified to use majority voting to segment bias corrected T1-weighted uniform (MP2-UNI) images. Thalamic nuclei from MP2-SYN and MP2-UNI images were evaluated against corresponding nuclei obtained from WMn-MPRAGE images using dice coefficients, volume similarity indices (VSIs) and distance between centroids. RESULTS: For MP2-SYN, dice > 0.85 and VSI > 0.95 was achieved for five larger nuclei and dice > 0.6 and VSI > 0.7 was achieved for seven smaller nuclei. The dice and VSI were slightly higher, whereas the distance between centroids were smaller for MP2-SYN compared to MP2-UNI, indicating improved performance using the MP2-SYN image. CONCLUSIONS: THOMAS algorithm can successfully segment thalamic nuclei in MP2RAGE images with essentially equivalent quality as WMn-MPRAGE, widening its applicability in studies focused on thalamic involvement in aging and disease.

Structural correlates of atypical visual and motor cortical oscillations in pediatric-onset multiple sclerosis.

We have previously demonstrated that pediatric-onset multiple sclerosis (POMS) negatively impacts the visual pathway as well as motor processing speed. Relationships between MS-related diffuse structural damage of gray and white matter (WM) tissue and cortical responses to visual and motor stimuli remain poorly understood. We used magnetoencephalography in 14 POMS patients and 15 age- and sex-matched healthy controls to assess visual gamma (30-80 Hz), motor gamma (60-90 Hz), and motor beta (15-30 Hz) cortical oscillatory responses to a visual-motor task. Then, 3T MRI was used to: (a) calculate fractional anisotropy (FA) of the posterior visual and corticospinal motor WM pathways and (b) quantify volume and thickness of the cuneus and primary motor cortex. Visual gamma band power was reduced in POMS and was associated with reduced FA of the optic radiations but not with loss of cuneus volume or thickness. Activity in the primary motor cortex, as measured by postmovement beta rebound amplitude associated with peak latency, was decreased in POMS, although this reduction was not predicted by structural metrics. Our findings implicate loss of WM integrity as a contributor to reduced electrical responses in the visual cortex in POMS. Future work in larger cohorts will inform on the cognitive implications of this finding in terms of visual processing function and will determine whether the progressive loss of brain volume known to occur in POMS ultimately contributes to both progressive dysfunction in such tasks as well as progressive reduction in cortical electrical responses in the visual cortex.

Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines.

MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.

High- and Low-Contrast Letter Acuity Perception Matures With Age in Normally Sighted Children.

BACKGROUND: High-contrast visual acuity (HCVA) changes with age, yet little is known about pediatric-specific age- and sex-normative values for low-contrast letter acuity (LCLA). We define maturational changes in monocular and binocular HCVA and LCLA in childhood and adolescence. METHODS: Normally sighted youth (ages 5-20 years, without neurologic or ophthalmologic disease and best-corrected HCVA of 20/25 or better in each eye) were recruited. Mean monocular and binocular scores using Early Treatment Diabetic Retinopathy Study (for HCVA) and 2.5% and 1.25% Sloan (for LCLA) charts and the magnitude of binocular summation were calculated using 2-year bins. Relationships between scores and age were explored using scatterplots with Locally Weighted Scatterplot Smoothing (LOWESS) and analysis of variance that accounts for intereye correlation, followed by test of linear trend for age effect. RESULTS: Among 101 (202 eyes) healthy participants (mean age 13 years, 42% males), monocular and binocular scores varied by age, with highest mean scores achieved in the 13 to 14-year age group for both HCVA and LCLA. Between the ages of 5 and 14.9 years, monocular scores increased linearly with age (0.76 letter/year for HCVA, 1.11 letters/year for 2.5% LCLA, and 0.97 letter/year for 1.25% LCLA; all P < 0.0001). Binocular HCVA scores also increased with age between 5 and 14.9 years (0.71 letters/year, P < 0.0001). The magnitude of binocular summation for HCVA or LCLA did not change with age. CONCLUSIONS: HCVA and LCLA abilities mature into adolescence, peak between 13 and 14.9 years of age, and then plateau into adulthood. Evaluation of patients with visual deficits should consider age-expected normal visual acuity.

Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis.

BACKGROUND: Adherence to disease-modifying therapies (DMTs) in pediatric multiple sclerosis (MS) is not well understood. We examined the prevalence and risk factors for poor adherence in pediatric MS. METHODS: This cross-sectional study recruited youth with MS from 12 North American pediatric MS clinics. In addition to pharmacy-refill data, patients and parents completed self-report measures of adherence and quality of life. Additionally, patients completed measures of self-efficacy and well-being. Factor analysis and linear regression methods were used. RESULTS: A total of 66 youth (mean age, 15.7 years) received MS DMTs (33% oral, 66% injectable). Estimates of poor adherence (i.e. missing >20% of doses) varied by source: pharmacy 7%, parent 14%, and patient 41%. Factor analysis yielded two composites: adherence summary and parental involvement in adherence. Regressions revealed that patients with better self-reported physical functioning were more adherent. Parents were more likely to be involved in adherence when their child had worse parent-reported PedsQL School Functioning and lower MS Self-Efficacy Control. Oral DMTs were associated with lesser parental involvement in adherence. CONCLUSION: Rates of non-adherence varied by information source. Better self-reported physical functioning was the strongest predictor of adherence. Parental involvement in adherence was associated with worse PedsQL School Functioning and lower MS Self-Efficacy-measured confidence in controlling MS.

Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances.

Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task-based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS.

Correction to: Impact of an electronic monitoring device and behavioural feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial.

The clinicaltrials.gov identifying number for the article titled "Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial" is NCT02234713 (https://clinicaltrials.gov/ct2/show/NCT02234713).

Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial.

PURPOSE: To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS. METHODS: Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen's effect size computation evaluated intervention impact. RESULTS: Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = -0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen's d = -0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = -0.58) and six months (d = -0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = -0.53 at 6 months) and environmental mastery (d = -0.42 at 3 and 6 months) in intervention as compared to control patients. CONCLUSIONS: Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being.

Electrographic Seizures in Children and Neonates Undergoing Extracorporeal Membrane Oxygenation.

OBJECTIVE: We aimed to determine the prevalence and risk factors for electrographic seizures in neonates and children requiring extracorporeal membrane oxygenation support. DESIGN: Prospective quality improvement project. SETTING: Quaternary care pediatric institution. PATIENTS: Consistent with American Clinical Neurophysiology Society electroencephalographic monitoring recommendations, neonates and children requiring extracorporeal membrane oxygenation support underwent clinically indicated electroencephalographic monitoring. INTERVENTIONS: We performed a 2-year quality improvement study from July 2013 to June 2015 evaluating electrographic seizure prevalence and risk factors. MAIN RESULTS: Ninety-nine of 112 patients (88%) requiring extracorporeal membrane oxygenation support underwent electroencephalographic monitoring. Electrographic seizures occurred in 18 patients (18%), of whom 11 patients (61%) had electrographic status epilepticus and 15 patients (83%) had exclusively electrographic-only seizures. Electrographic seizures were more common in patients with low cardiac output syndrome (p = 0.03). Patients with electrographic seizures were more likely to die prior to discharge (72% vs 30%; p = 0.01) and have unfavorable outcomes (54% vs 17%; p = 0.004) than those without electrographic seizures. CONCLUSIONS: Electrographic seizures occurred in 18% of neonates and children requiring extracorporeal membrane oxygenation support, often constituted electrographic status epilepticus, and were often electrographic-only thereby requiring electroencephalographic monitoring for identification. Low cardiac output syndrome was associated with an increased risk for electrographic seizures. Electrographic seizures were associated with higher mortality and unfavorable outcomes. Further investigation is needed to determine whether electrographic seizures identification and management improves outcomes.

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.

Age of onset as a moderator of cognitive decline in pediatric-onset multiple sclerosis.

Cognitive impairment is often reported in pediatric-onset multiple sclerosis (MS). Using serial cognitive data from 35 individuals with pediatric-onset MS, this study examined how age at disease-onset and proxies of cognitive reserve may impact cognitive maturation over the course of childhood and adolescence. Neuropsychological evaluations were conducted at baseline and up to four more assessments. Of the 35 participants, 7 completed only one assessment, 5 completed two assessments, 13 completed three assessments, 10 completed four or more assessments. Growth curve modeling was used to assess longitudinal trajectories on the Trail Making Test-Part B (TMT-B) and the Symbol Digit Modalities (SDMT; oral version) and to examine how age at disease onset, baseline Full Scale IQ, and social status may moderate rate of change on these measures. Mean number of evaluations completed per patient was 2.8. Younger age at disease onset was associated with a greater likelihood of cognitive decline on both the TMT-B (p=.001) and SDMT (p=.005). Baseline IQ and parental social status did not moderate any of the cognitive trajectories. Findings suggest that younger age at disease-onset increases the vulnerability for disrupted performance on measures of information processing, visual scanning, perceptual/motor speed, and working memory. Proxies of cognitive reserve did not protect against the progression of decline on these measures. Young patients with MS should be advised to seek follow-up cognitive evaluation to assess cognitive maturation and to screen for the potential late emergence of cognitive deficits. (JINS, 2014, 20, 1-9).

Sex ratio and age of onset in AQP4 antibody-associated NMOSD: a review and meta-analysis.

BACKGROUND: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. METHODS: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. RESULTS: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. CONCLUSIONS: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

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.

Differential diagnosis of suspected multiple sclerosis: an updated consensus approach.

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.