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Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The 2009 and revised 2023 RIS criteria were developed for diagnosis. Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3-4 of 4 dissemination in space McDonald 2005 MS criteria are still diagnosed with RIS using the revised 2023 RIS criteria. In presymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers, CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown., Objective: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests., Methods: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race)., Results: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03)., Conclusions: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are highly suggestive of multiple sclerosis but their clinical history does not include symptoms consistent with multiple sclerosis. Data from international longitudinal cohorts indicate that around half of people with RIS will develop relapsing or progressive symptoms of multiple sclerosis within 10 years, suggesting that in some individuals, RIS is a presymptomatic stage of multiple sclerosis. Risk factors for progression from RIS to clinical multiple sclerosis include younger age (ie, <35 years), male sex, CSF-restricted oligoclonal bands, spinal cord or infratentorial lesions, and gadolinium-enhancing lesions. Other imaging, biological, genetic, and digital biomarkers that might be of value in identifying individuals who are at the highest risk of developing multiple sclerosis need further investigation. Two 2-year randomised clinical trials showed the efficacy of approved multiple sclerosis immunomodulatory medications in preventing the clinical conversion to multiple sclerosis in some individuals with RIS. If substantiated in longer-term studies, these data have the potential to transform our approach to care for the people with RIS who are at the greatest risk of diagnosis with multiple sclerosis., Competing Interests: Declaration of interests CL-F is the principal investigator of the TERIS study. OK declares no competing interests. AS has received research grants from The Turkish Multiple Sclerosis Society and The Scientific and Technological Research Council Of Turkey and Istanbul University-Cerrahpasa Research Support Funds. He has received consultancy fees from Roche, Merck Serono, Biogen Idec/Gen Pharma of Turkey, Sanofi-Genzyme, Novartis, and Alexion, has received honoraria for lectures from Sanofi-Genzyme, Novartis, Roche, and Teva, and has received registration coverage for attending scientific congresses or symposia from Sanofi-Genzyme and Alexion. CJA receives grant support from the National Multiple Sclerosis Society and the National Institutes of Health (NIH). In the past 3 years, she has received honoraria or consulting fees from Sanofi-Genzyme, Novartis, Genentech, Alexion, EMD Serono, and Horizon Therapeutics for participation on advisory boards and data safety monitoring committees, and honoraria for lectures from the American Academy of Neurology, Spire Learning, Department of Defense, Catamount Education, Projects in Knowledge, and Oregon Health and Science University. NM has received research funding from the NIH (award number K23NS101099), the National Multiple Sclerosis Society, and the Charles H Hood Foundation, and speaker honoraria for MDedge. DP has received consulting honoraria from Roche and Novartis. DTO received personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, and Viela Bio, and research support from Biogen and Merck Serono. He was also a study protocol author and served as the lead investigator of the ARISE study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Pain in multiple sclerosis (MS) is common, but literature on pain in children with MS remains scarce. Pain has physical, psychological, and social implications in MS, and both comprehensive assessment and interdisciplinary management approaches are needed. We sought to develop an interdisciplinary interim guideline for the assessment and management of pain in children with MS., Methods and Materials: We convened a modified Delphi panel composed of 13 experts in pediatric and adult MS neurology, physiotherapy, pain, patient lived-experience, advanced practice nursing, psychology, physiatry, and MS research. A survey was sent to panelists for anonymous completion. The panel discussed survey themes extracted by the panel chair. The process was repeated twice., Results: Thirteen assessment and treatment recommendations were produced regarding pain in children with MS., Discussion: Future studies will assess implementation of these pain assessment and treatment guidelines in the clinical setting., Competing Interests: Makhani is a consultant for the Institute for Advanced Clinical Trials for Children. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stratton, Vassilopoulos, Brenton, Potter, Vargas, Rumm, Bartels, Bailey, Odonkor, Stoll, Zempsky, Yeh and Makhani.)

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Radiologically isolated syndrome refers to the clinical scenario in which individuals have imaging concerning for multiple sclerosis and would otherwise satisfy radiographic dissemination in space criteria, but do not have any attributable signs or symptoms. Radiologically isolated syndrome has been increasingly recognized in the pediatric population and it is understood certain individuals will transition to a formal diagnosis of multiple sclerosis over time. This review aims to outline the available data within this unique population including the diagnostic criteria, epidemiology, risk factors associated with transitioning to multiple sclerosis, and the current therapeutic landscape. Radiologically isolated syndrome will also be positioned within a broader spectrum of demyelinating disease as recent data has pointed towards a likely prodromal phase that precedes a first clinical event and diagnosis of multiple sclerosis. Characterizing the radiographic features, clinical symptoms, and biomarkers that constitute this prodromal phase of multiple sclerosis would help identify patients who may most benefit from early intervention in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.

Objectives: To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition., Study Design: This was a retrospective multicenter study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention's case definition., Results: In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, -2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, -4 to -2; P < .001)., Conclusions: Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome., (© 2022. Springer Nature Limited.)

Patients with a historical diagnosis of multiple sclerosis (MS)-a patient presenting with a diagnosis of MS made previously and by a different clinician-present specific diagnostic and therapeutic challenges in clinical practice. Application of the McDonald criteria is most straightforward when applied contemporaneously with a syndrome typical of an MS attack or relapse; however, retrospective application of the criteria in some patients with a historical diagnosis of MS can be problematic. Limited patient recollection of symptoms and evolution of neurologic examination and MRI findings complicate confirmation of an earlier MS diagnosis and assessment of subsequent disease activity or clinical progression. Adequate records for review of prior clinical examinations, laboratory results, and/or MRI scans obtained at the time of diagnosis or during ensuing care may be inadequate or unavailable. This article provides recommendations for a clinical approach to the evaluation of patients with a historical diagnosis of MS to aid diagnostic confirmation, avoid misdiagnosis, and inform therapeutic decision making., (© 2022 American Academy of Neurology.)

A growing body of work points toward the existence of a clinically symptomatic prodromal phase in multiple sclerosis (MS) that might span 5-10 years or more. A prodrome is an early set of signs or symptoms predating the onset of classical disease, which in turn predates a definitive diagnosis. Evidence for a prodromal phase in MS could have major implications for prevention, earlier recognition and treatment, as well as an improved disease course or prognosis. This Perspective provides a succinct overview of the recent advances in our understanding of the MS prodrome and current key challenges. Many of the MS prodromal features characterized thus far are non-specific and are common in the general population; no single feature alone is sufficient to identify an individual with prodromal MS. Biomarkers may increase specificity and accuracy for detecting individuals in the MS prodromal phase, but are yet to be discovered or formally validated. Progress made in the elucidation of prodromal phases in other neurological and immune-mediated diseases suggests that these barriers can be overcome. Therefore, while knowledge of a prodromal phase in MS remains nascent, how best to move from the rapidly growing evidence to research-related action is critical. Immediate implications include refining the concept of the MS continuum to include a prodromal phase. This will help inform the true "at risk" period when considering exposures that might cause MS. Major long-term implications include the earlier recognition of MS, improved prognosis, through earlier disease management, and the future possibility of MS disease prevention., Competing Interests: NM was funded by NIH/NINDS (Grant No. K23NS101099) and the Charles H. Hood Foundation. KM was funded by NIH/NINDS and the US Department of Defense. She has received travel expenses to participate in conferences from the National MS Society (2019, 2020) and ECTRIMS/ACTRIMS (2018, 2019). She was a paid consultant for serving on a scientific advisory committee (Biogen, 2020). HT was the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support received from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation. In addition, in the last 5 years, has received research support from the UK MS Trust; travel expenses to present at CME conferences from the Consortium of MS Centres (2018), the National MS Society (2016, 2018), ECTRIMS/ACTRIMS (2015–2020), American Academy of Neurology (2015, 2016, 2019). Speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by HT's research group. Unrelated to this study NM receives funding from the Charles H. Hood Foundation., (Copyright © 2022 Tremlett, Munger and Makhani.)

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown., Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria., Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021., Exposure: Diagnosis of RIS., Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors., Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%., Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

A prodrome is an early set of signs, symptoms or other findings that occur before the onset of typical symptoms of a disease. Prodromal phases are well recognized in several neurological and inflammatory diseases, but the possibility of a prodrome in multiple sclerosis (MS) has received relatively little attention until the past few years. In this Perspective, we summarize what is currently known about the MS prodrome, including its possible duration, clinical features and potential biomarkers. We also consider what insights and lessons can be learned from knowledge of and research into the prodromal phases of other diseases. A better understanding of the MS prodrome could have profound clinical implications as it could enable earlier recognition of MS and earlier initiation of treatments that reduce relapse rates and long-term disability. Knowledge of the MS prodrome could also affect research into the causes of MS, and putative risk factors must be re-evaluated in light of the MS prodrome. We conclude by outlining the major knowledge gaps and propose future initiatives., (© 2021. Springer Nature Limited.)

Multiple sclerosis is being increasingly recognized and diagnosed in children. In the past several years, advances have been made in diagnosing multiple sclerosis in children, identifying new genetic and environmental risk factors, delineating underlying immunobiology, characterizing imaging findings, and implementing new treatment strategies. In this review, we discuss these advances. Future research into the determinants of multiple sclerosis in children and into new treatment options will be aided by continued international collaboration., Competing Interests: N.M. reports grants from NIH/NINDS, during the conduct of the study., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose of Review: This review provides the reader with updated information needed to make an accurate diagnosis of radiologically isolated syndrome (RIS), discusses controversies and considerations related to therapeutic intervention in RIS, and summarizes ongoing clinical intervention trials., Recent Findings: Individuals with RIS lack clinical neurological symptoms but are at risk for the subsequent development of a first clinical neurological event consistent with a diagnosis of multiple sclerosis. There are two ongoing clinical intervention trials to determine whether disease-modifying treatments for multiple sclerosis can delay or prevent a first clinical event in individuals with RIS. If clinical trials demonstrate a beneficial effect of disease-modifying therapy, such interventions should be considered in individuals with RIS.

Objective: To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM)., Methods: A multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength., Results: Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] -1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients ( p = 0.015)., Conclusion: Fluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes., Classification of Evidence: This study provides Class IV evidence that for patients with EV-D68-associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes., (© 2018 American Academy of Neurology.)

Background: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination., Objectives: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome., Methods: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria., Results: Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%)., Conclusions: Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.

Objective: To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed "radiologically isolated syndrome" or RIS)., Methods: Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS., Results: We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%-60%) in a median of 2.0 years (interquartile range [IQR] 1.0-4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%-76%) in a median of 1.1 years (IQR 0.5-1.9 years). The presence of ≥2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4-86.2, p = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4-43.6, p = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex., Conclusions: We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.

Background: Miller Fisher syndrome (MFS) is a rare demyelinating condition which may have involvement of cranial nerves. There are a few case reports of optic pathway involvement in children. We describe 3 patients with optic pathway enhancement in pediatric patients with MFS., Case Series: We retrospectively reviewed brain imaging findings in 17 pediatric patients with of Guillain-Barré syndrome (GBS) meeting Brighton criteria who had brain MRIs performed during their acute illness. Cranial nerve enhancement was seen in 6/17 patients and optic nerve/chiasm enhancement was seen in 3 patients., Conclusion: Cranial nerve enhancement and optic pathway in particular, can be seen in patients with MFS. Imaging findings do not always correlate with clinical manifestations of cranial nerve involvement., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program, "The World of Pediatric MS: A Global Update," in September 2014 to discuss advances and challenges in the diagnosis and management of pediatric multiple sclerosis (MS) and other neuroinflammatory CNS disorders. Highlights included a discussion on the revised diagnostic criteria, which enable the differentiation of MS, acute disseminated encephalomyelitis, neuromyelitis optica, and other neuroinflammatory disorders. While these criteria currently identify clinical and MRI features for a particular diagnosis, advances in biomarkers may prove to be useful in the future. An update was also provided on environmental factors associated with pediatric MS risk and possibly outcomes, notably vitamin D deficiency. However, optimal vitamin D intake and its role in altering MS course in children have yet to be established. Regarding MS outcomes, our understanding of the cognitive consequences of early-onset MS has grown. However, further work is needed to define the course of cognitive function and its long-term outcome in diverse patient samples and to develop strategies for effective cognitive rehabilitation specifically tailored to children and adolescents. Finally, treatment strategies were discussed, including a need to consider additional drug treatment options and paradigms (escalation vs induction), although treatment should be tailored to the individual child. Of critical importance, clinical trials of newer MS agents in children are required. Although our understanding of childhood MS has improved, further research is needed to have a positive impact for children and their families., (© 2016 American Academy of Neurology.)

Many disease-modifying therapies are currently available for adults with relapsing-remitting multiple sclerosis (MS) but none of them has been tested in pediatric MS in randomized placebo-controlled trials. At present, as suggested by observational studies and experts' guidelines, interferon-β and glatiramer acetate continue to be the standard first-line treatments for pediatric MS. Observational studies and some controlled unblinded trials have shown a positive effect of these meditations in reducing relapse rate and delaying disease progression, with an acceptable safety profile. The goal of this article is to provide an overview of current knowledge with regard to safety, tolerability, and efficacy of first-line treatment options for MS in the pediatric age group, with the aim of providing guidance for planning first-line treatment of MS in children and adolescents., (© 2016 American Academy of Neurology.)

Background: First-line injectable therapies for multiple sclerosis in children may be ineffective or not well-tolerated. There is therefore an urgent need to explore oral medications for pediatric multiple sclerosis. We review our dual-center experience with oral dimethyl fumarate., Methods: This study was a retrospective review of children 18 years of age or less with multiple sclerosis treated with dimethyl fumarate at Yale University and the University of Colorado. Clinical, demographic, and magnetic resonance imaging parameters were analyzed., Results: We identified 13 children treated with oral dimethyl fumarate for a median of 15.0 months (range, 1 to 25). Dimethyl fumarate was utilized as first-line therapy in five children (38%). Ten children (77%) tolerated dose escalation to the usual adult dose of 240 mg twice daily. Nine children had ≥12 months of follow-up on treatment. Eight of nine (89%) displayed stabilized or reduced relapse rates and disability scores on treatment. Nine children underwent brain magnetic resonance imaging performed after 12 or more months of therapy. New T2 lesions were observed in three children (33%), one of whom had been nonadherent to treatment. Common side effects included facial flushing (8/13, 62%), gastrointestinal discomfort (7/13, 54%), rash (3/13, 23%), and malaise (2/13, 15%). Three children (23%) discontinued treatment because of side effects. No patients displayed laboratory abnormalities including lymphopenia or abnormal liver transaminases. There were no reported infections., Conclusions: Oral dimethyl fumarate appears to be safe and generally well tolerated in children with multiple sclerosis. Formal clinical trials to evaluate efficacy are ongoing., (Copyright © 2016 Elsevier Inc. All rights reserved.)