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Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk ( PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene ( PRF1, p = 2.70 × 10−3) and two MHC genes ( BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA- DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 ( DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence ofDRB1*15and the absence ofA*02,and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, includingIL-6(rs2069852),BCL-2(rs2187163) andNFKB1(rs7665090).Results490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, pNFKB1SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence ofHLA-A*02(AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products andNFKB1SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found withIL-6andBCL-2SNP GG genotypes.ConclusionsThe presence of gene–environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

Neuromyelitis optica spectrum disorder is an inflammatory condition of the central nervous system typically manifesting as myelitis, optic neuritis, and/or area postrema syndrome. Here, we present a pediatric patient who developed symptoms consistent with area postrema syndrome with positive anti-aquaporin-4 (AQP4) antibodies who was also found to have an ovarian teratoma. Pathological specimens revealed the presence of aquaporin-4. This was felt to be the antigenic trigger that led to the patient’s condition. She suffered no further clinical attacks and seroconverted to negative AQP4 status upon teratoma removal. This case varies from others, in that the paraneoplastic presentation occurred in a pediatric patient and in that the patient has not required maintenance immunotherapy after teratoma removal.

Background: The current landscape and treatment patterns of disease-modifying therapy (DMT) use in pediatric patients with multiple sclerosis (MS) are not yet well understood. This study examined DMT utilization and treatment patterns in pediatric patients newly diagnosed as having MS. Methods: Pediatric patients ( Results: Of 182,057 patients newly diagnosed as having MS, 288 pediatric patients (mean age, 14 years; 61% female) were identified. Within the first year of diagnosis, 188 patients (65.3%) did not receive any DMT. The most common first-initiated treatments were interferons and glatiramer acetate (83%), but 28% of patients switched or discontinued from first-initiated treatment within 6 months of treatment initiation. Conclusions: This study suggests that a considerable proportion of pediatric patients with MS remain untreated within 1 year of diagnosis. Patients most commonly initiated injectables as their first DMT. Overall, therapy failed early in approximately one in three patients. Thus, the study warrants urgency in treating these patients with currently approved treatment options.

BackgroundOptical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort.MethodsPOMS (defined using consensus criteria and first attack 6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness 5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON.ResultsA total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm).ConclusionsIn POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON.

Background and ObjectivesA descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod.MethodsWe reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020.ResultsAs of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11–69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31–70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients.DiscussionBased on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Author(s): Greenberg, Benjamin M; Casper, Theron Charles; Mar, Soe S; Ness, Jayne M; Plumb, Patricia; Liang, Shannon; Goyal, Manu; Weinstock-Guttman, Bianca; Rodriguez, Moses; Aaen, Gregory S; Belman, Anita; Barcellos, Lisa F; Rose, John W; Gorman, Mark P; Benson, Leslie A; Candee, Meghan; Chitnis, Tanuja; Harris, Yolanda C; Kahn, Ilana L; Roalstad, Shelly; Hart, Janace; Lotze, Timothy E; Rensel, Mary; Rubin, Jennifer P; Schreiner, Teri L; Tillema, Jan-Mendelt; Waldman, Amy Tara; Krupp, Lauren; Graves, Jennifer; Drake, Kaylea; Waubant, Emmanuelle | Abstract: Background and objectiveThe objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls.MethodsData collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls.ResultsThere was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p l 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives.DiscussionThe increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.

Background and ObjectivesOpsoclonus-myoclonus syndrome (OMS) is a rare autoimmune disorder associated with neuroblastoma in children, although idiopathic and postinfectious etiologies are present in children and adults. Small cohort studies in homogenous populations have revealed elevated rates of autoimmunity in family members of patients with OMS, although no differentiation between paraneoplastic and nonparaneoplastic forms has been performed. The objective of this study was to investigate the prevalence of autoimmune disease in first-degree relatives of pediatric patients with paraneoplastic and nonparaneoplastic OMS.MethodsA single-center cohort study of consecutively evaluated children with OMS was performed. Parents of patients were prospectively administered surveys on familial autoimmune disease. Rates of autoimmune disease in first-degree relatives of pediatric patients with OMS were compared using Fisher exact t test and χ2 analysis: (1) between those with and without a paraneoplastic cause and (2) between healthy and disease (pediatric multiple sclerosis [MS]) controls from the United States Pediatric MS Network.ResultsThirty-five patients (18 paraneoplastic, median age at onset 19.0 months; 17 idiopathic, median age at onset 25.0 months) and 68 first-degree relatives (median age 41.9 years) were enrolled. One patient developed systemic lupus erythematosus 7 years after OMS onset. Paraneoplastic OMS was associated with a 50% rate of autoimmune disease in a first-degree relative compared with 29% in idiopathic OMS (p = 0.31). The rate of first-degree relative autoimmune disease per OMS case (14/35, 40%) was higher than healthy controls (86/709, 12%; p < 0.001) and children with pediatric MS (101/495, 20%; p = 0.007).DiscussionIn a cohort of pediatric patients with OMS, there were elevated rates of first-degree relative autoimmune disease, with no difference in rates observed between paraneoplastic and idiopathic etiologies, suggesting an autoimmune genetic contribution to the development of OMS 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.

Autoimmune myelitis is an inflammatory reaction in the spinal cord leading to acute and subacute motor, sensory, or autonomic disturbances. Once compressive and infectious etiologies for myelopathies are excluded, the treatment approach is very similar. The diagnostic evaluation is often more challenging as no single test can provide certainty of the etiology. However, the combination of clinical presentation, radiological features, spinal fluid analysis, and serological testing can elucidate likely causes and guide management.

Current treatments for antibody-mediated autoimmunity are associated with lack of specificity, leading to immunosuppressive effects. To overcome this limitation, we have developed a class of antibody-based therapeutics for the treatment of autoimmunity involving antibodies that recognize the autoantigen, myelin oligodendrocyte glycoprotein (MOG). These agents ("Seldegs," for selective degradation) selectively eliminate antigen (MOG)-specific antibodies without affecting the levels of antibodies of other specificities. Seldeg treatment of mice during antibody-mediated exacerbation of experimental autoimmune encephalomyelitis by patient-derived MOG-specific antibodies results in disease amelioration. Consistent with their therapeutic effects, Seldegs deliver their targeted antibodies to Kupffer and liver sinusoidal endothelial cells that are known to have tolerogenic effects. Our results show that Seldegs can ameliorate disease mediated by MOG-specific antibodies and indicate that this approach also has the potential to treat other autoimmune diseases where the specific clearance of antibodies is required.

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG MS study ( N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. Results: With fingolimod, ALC rapidly reduced to 29.9%–34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2–0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC 9/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Objective:The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children.Methods:DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard.Results:Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = −17.5, −4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively.Conclusion:The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Objective: To compare relapse rates and healthcare costs in MS patients treated with Glatopa 20 mg (generic glatiramer acetate) versus Copaxone 20 mg in a US managed care population. Methods: A retrospective claims study was conducted using the HealthCore Integrated Research Database. Patients with ≥1 Glatopa or Copaxone claim between 01 April 2015 (Glatopa) or 01 January 2013 (Copaxone) and 30 April 2018 were included. Patients with prior Copaxone 40 mg use or Results: A total of 357 Glatopa and 2291 Copaxone patients qualified for inclusion; 158 per cohort were retained after matching. Baseline characteristics were well-balanced (mean age 49.9 years, 75% female, mean 3.8 Copaxone fills). At baseline, 8% of patients had ≥1 relapse with mean annualized relapse rates (ARR) of 0.18; at follow-up, the relapse rates were 8% versus 15% (Glatopa versus Copaxone; p = .05), and ARRs were 0.12 versus 0.30 (p = .05). 45% of Glatopa patients switched (back) to Copaxone 20/40 mg and were censored at that point. Mean (SD) all-cause medical and pharmacy costs were $51,507 ($28,494) versus $55,085 ($37,061; p = .50). Mean MS-related costs were $45,379 ($24,732) versus $47,949 ($32,615; p = .67), of which mean disease modifying therapy costs were $42,926 ($23,196) versus $44,932 ($28,554; p = .59). Results were similar in sensitivity analyses. Conclusions: In this real-world study, MS patients treated with Glatopa experienced similar health outcomes and costs compared to those treated with Copaxone, with a trend towards lower relapse rates (borderline statistically significant) and cost savings (not statistically significant).

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Background We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. Methods Pediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case–control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk‐Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. Results Fine particulate matter (PM 2.5), carbon monoxide (CO), sulfur dioxide (SO 2), and lead air emissions were associated with increased odds for pediatric MS (P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls. Conclusion Out of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO 2, CO, and lead) were statistically associated with higher odds for pediatric MS.

Objective While prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. Methods Cases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status. Results A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status. Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Background Anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders frequently manifest as optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. While their clinical phenotypes overlap with relapsing inflammatory Central nervous system (CNS) conditions such as multiple sclerosis and neuromyelitis optica spectrum disorder, MOG-related syndromes frequently occur in a younger age group. In children, longitudinally extensive transverse myelitis (LETM) is less specific for anti-aquaporin-4 associated neuromyelitis optica spectrum disorder, and has also been reported in pediatric multiple sclerosis, idiopathic transverse myelitis, and acute flaccid myelitis. Methods We summarize two patients with positive MOG antibodies and myelitis. Results We identified two individuals with anti-MOG associated LETM that demonstrate primarily gray matter involvement. Clinically these patients exhibited hyperreflexia and had rapid improvement with immunotherapies. Conclusions Anti-MOG diseases can cause LETM with gray matter predominance mimicking acute flaccid myelitis, but clinically these patients can have retained reflexes and respond favorably to immunotherapies.

Pediatric-onset multiple sclerosis (MS) is a rare but increasingly recognized condition that both parallels and diverges from adult-onset MS. Exposure to key risk determinants for MS disease pathogenesis may occur during childhood. The diagnosis of pediatric MS can be challenging due to potential for atypical presentations and a broad differential diagnosis. MS disease-modifying therapies have not been rigorously studied in children and raise difficult questions on how to manage a chronic inflammatory neurologic disease in a population of patients with developing central nervous and immune systems.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p −16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p −16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Background Deep sequencing of lymphocyte receptor repertoires has made it possible to comprehensively profile the clonal composition of lymphocyte populations. This opens the door for novel approaches to diagnose and prognosticate diseases with a driving immune component by identifying repertoire sequence patterns associated with clinical phenotypes. Indeed, recent studies support the feasibility of this, demonstrating an association between repertoire-level summary statistics (e.g., diversity) and patient outcomes for several diseases. In our own prior work, we have shown that six codons in VH4-containing genes in B cells from the cerebrospinal fluid of patients with relapsing remitting multiple sclerosis (RRMS) have higher replacement mutation frequencies than observed in healthy controls or patients with other neurological diseases. However, prior methods to date have been limited to focusing on repertoire-level summary statistics, ignoring the vast amounts of information in the millions of individual immune receptors comprising a repertoire. We have developed a novel method that addresses this limitation by using innovative approaches for accommodating the extraordinary sequence diversity of immune receptors and widely used machine learning approaches. We applied our method to RRMS, an autoimmune disease that is notoriously difficult to diagnose. Results We use the biochemical features encoded by the complementarity determining region 3 of each B cell receptor heavy chain in every patient repertoire as input to a detector function, which is fit to give the correct diagnosis for each patient using maximum likelihood optimization methods. The resulting statistical classifier assigns patients to one of two diagnosis categories, RRMS or other neurological disease, with 87% accuracy by leave-one-out cross-validation on training data (N = 23) and 72% accuracy on unused data from a separate study (N = 102). Conclusions Our method is the first to apply statistical learning to immune repertoires to aid disease diagnosis, learning repertoire-level labels from the set of individual immune repertoire sequences. This method produced a repertoire-based statistical classifier for diagnosing RRMS that provides a high degree of diagnostic capability, rivaling the accuracy of diagnosis by a clinical expert. Additionally, this method points to a diagnostic biochemical motif in the antibodies of RRMS patients, which may offer insight into the disease process. Electronic supplementary material The online version of this article (10.1186/s12859-017-1814-6) contains supplementary material, which is available to authorized users.

Background: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. Objective: To determine the association between dietary factors and MS in children. Methods: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, Results: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p Conclusion: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

Background Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. Objective To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. Methods The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). Results We included 271 cases (mean age at disease onset of 15.7 years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p = 0.01). Conclusions While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

Background At sufficiently high doses, methotrexate (HDMTX) achieves substantial CNS penetration, whereas other tissues can be rescued from the effects of HDMTX by leucovorin rescue (LR), which does not penetrate the blood-brain barrier. Objectives To report on the efficacy and safety of HDMTX with LR (HDMTX-LR), in the treatment of acute demyelinating inflammatory CNS syndromes refractory to conventional immunotherapy. Methods We performed a retrospective chart review of 12 patients treated (6 multiple sclerosis [MS], 4 neuromyelitis optica [NMO], and 2 Sjogren's syndrome myelopathy [SSM]) with HDMTX-LR after failing to improve, or exhibiting worsening following conventional immunotherapy. 11 patients were followed for a total of 6 months following HDMTX-LR (one was lost to follow up after 1 month); and clinical findings were documented at 1 month, 3 months, and 6 months following HDMTX-LR therapy. Results Ten patients demonstrated both clinical and radiologic evidence of near, if not complete, abolishment of disease activity, in conjunction with impressive reconstitution of neurologic function in the 6-month period following HDMTX-LR. Mean Kurtzke Expanded Disability Status Scale (EDSS) prior to HDMTX-LR was 8.1 (± 1.4). Following HDMTX-LR, mean EDSS was 6.6 (± 2.4) at 1 month, 5.8 (± 2.3) at 3 months, and 5.7 (± 2.3) at 6 months. Conclusions In this retrospective assessment of treatment-recalcitrant fulminant inflammatory CNS syndromes, HDMTX-LR was observed to be a safe and highly effective treatment, producing the rapid and near complete cessation of disease activity, in conjunction with an important corresponding and ‘durable remission’ in the majority of our small treatment cohort.

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-β-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease.

Pediatric transverse myelitis (TM) is an acquired, immune-mediated disorder that leads to injury of the spinal cord and often manifests as weakness, numbness, bowel dysfunction, and/or bladder dysfunction. Multiple etiologies for myelitis can result in a similar clinical presentation, including idiopathic transverse myelitis (TM), multiple sclerosis (MS), neuromyeltis optica spectrum disorder (NMOSD) associated with anti-aquaporin 4 antibodies, MOG antibody-associated disease, and acute flaccid myelitis (AFM). Diagnosis relies on clinical recognition of the syndrome and confirming inflammation through imaging and/or laboratory studies. Acute treatment is targeted at decreasing immune-mediated injury, and chronic preventative therapy may be indicated if TM is determined to be a manifestation of a relapsing disorder (i.e., NMOSD). Timely recognition and treatment of acute transverse myelitis is essential, as it can be associated with significant morbidity and long-term disability.

Spinal cord involvement is an important cause of disability in patients with multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs can be distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations in the sensitivity and specificity of spinal cord imaging and poor correlation with disability megasures have impeded the understanding of the relationship between spinal cord involvement and clinical manifestations. Nevertheless, studies of the pathological features of multiple sclerosis and NMOSDs have shown that quantitatively different mechanisms lead to differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of these mechanisms is necessary to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor spinal cord involvement in the diagnosis and management of patients with multiple sclerosis or NMOSDs, and as outcome measures in clinical trials.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles., Author summary Multiple sclerosis (MS) is an autoimmune disease that is mostly found in populations with northern European ancestry. Our study investigates whether there is evidence that the difference in MS prevalence around the globe could be explained by European MS genetic risk factors in African Americans, Hispanics, or Asian Americans. Our work first established that most alleles associated with MS are not necessarily European, but are in fact, cosmopolitan. However, we also observed in African Americans that European HLA-DRB1*15:01 conferred three times the odds of MS compared to the African allele. The allele HLA-DRB1*15:01 has been shown to be a major genetic risk factor in Europeans and other admixed populations. In addition, we observed genetic variations between European and African HLA-DRB1*15:01 alleles that, based on location, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk or protective effects of other MS-associated alleles. Additionally, our study found on chromosome 8 in Hispanics a region where MS cases have more European ancestry than controls, implicating there may be new MS risk alleles to be discovered in Hispanics. In conclusion, our study found evidence that the difference in MS prevalence could be explained by European ancestry and established that the ancestry of MS genetic risk factors is complex.

Pediatric acute transverse myelitis (ATM) is an immune-mediated CNS disorder and contributes to 20% of children experiencing a first acquired demyelinating syndrome (ADS). ATM must be differentiated from other presentations of myelopathy and may be the first presentation of relapsing ADS such as neuromyelitis optica (NMO) or multiple sclerosis (MS). The tenets of the diagnostic criteria for ATM established by the Transverse Myelitis Consortium Working Group can generally be applied in children; however, a clear sensory level may not be evident in some. MRI lesions are often centrally located with high T2 signal intensity involving gray and neighboring white matter. Longitudinally extensive ATM occurs in the majority. Asymptomatic lesions on brain MRI are seen in more than one-third and predict MS or NMO. The role of antibodies such as myelin oligodendrocyte glycoprotein in monophasic and relapsing ATM and their significance in therapeutic approaches remain unclear. ATM is a potentially devastating condition with variable outcome and presents significant cumulative demands on health and social care resources. Children generally have a better outcome than adults, with one-half making a complete recovery by 2 years. There is need for standardization of clinical assessment and investigation protocols to enable international collaborative studies to delineate prognostic factors for disability and relapse. There are no robust controlled trials in children or adults to inform optimal treatment of ATM, with one study currently open to recruitment. This review provides an overview of current knowledge of clinical features, investigative workup, pathogenesis, and management of ATM and suggests future directions.

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate’s complex nature—being a chemically synthesized (ie, nonbiologic) mixture of peptides—the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Objective To evaluate predictors of renal deterioration (RD) in patients with multiple sclerosis (MS) at a tertiary referral center. Methods We reviewed adult patients with MS presenting for evaluation of lower urinary tract symptoms, with baseline urodynamic study (UDS) and either serum creatinine (SCr) or renal ultrasound, from a prospectively maintained database, and excluded patients with abnormal renal function. RD was defined as doubled SCr, new hydronephrosis, or renal atrophy on follow-up ultrasound. Demographic and UDS parameters were evaluated in multivariable models of RD. Results From 1999 to 2016, 660 patients were evaluated, and 355 met criteria with median follow-up of 79 months. SCr doubled in 8 patients, 4 had decline by renal ultrasound, and 1 by both (3%). Overall, 46 patients met less strict criteria of decrease in estimated glomerular filtration rate by ≥30%. Using the less rigid criterion, detrusor overactivity (DO) remained associated with RD on multivariable analysis. Eleven of 355 patients had RD by either imaging or doubled Cr, with which only history of diabetes mellitus and nephrolithiasis were associated. Conclusion By strict criteria, the rate of RD in patients with neurogenic bladder due to MS was low (3%) at intermediate-term follow-up and was not associated with UDS parameters. Using more liberal criteria, DO was associated with deterioration, suggesting that study of the impact of more aggressive control of DO in this population may be warranted.

Optic nerve involvement in anti-myelin oligodendrocyte glycoprotein antibody associated syndrome (MOG ab syndrome) tends to have unique features. Few studies have reported optical coherence tomography (OCT) measures like retinal nerve fiber layer thickness findings in the setting of pediatric MOG ab syndrome.The aim of this study is to compare visual acuity between MOG ab positive and MOG ab negative pediatric cohorts and examine correlations with OCT findings.We included outpatients less than 18 years of age who had optic neuritis (ON) of at least one eye and who completed visual testing and OCT in the study. ON was defined based on clinical or OCT findings. Antibody testing was obtained using cell-based assay. The primary analyses of interest investigated differences in low-contrast visual acuity stratified by the defined RNFL ranges and by antibody positivity.We analyzed 28 eyes from 14 anti-MOG ab patients (MOG-ON cohort), 18 eyes from 9 anti-AQP4 ab (AQP4-ON cohort) patients and 26 eyes from 13 patients who tested negative for both the antibodies (seronegative ON cohort). MOG-ON eyes with zero reported clinical events had lower RNFL thickness, than the minimum RNFL thickness of either the seronegative-ON or AQP4-ON eyes with zero clinical attacks in most retinal segments. Within the lowest range of the RNFL (RNFL50 um) in most retinal segments, the MOG-ON cohort had a statistically significant greater visual acuity relative to the AQP4 cohort.Patients with anti-MOG antibody mediated CNS disorders can suffer from subclinical ON events with significant reductions in RNFL. Despite equally significant damage to the optic nerve, MOG-Ab positive patients have relatively preserved visual acuity.

Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS., Neuromyelitis optica (NMO) is a rare autoimmune condition characterized by inflammation and demyelination of the optic nerve and the spinal cord. Here, Estrada et al. identify NMO susceptibility variants in the MHC region and find that autoantibody-positive NMO genetically overlaps with lupus.

Objective To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome. Methodology Case series. Results We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases. Discussion Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series. Conclusion In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome.

Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in ‘humanized’ mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

Background We have previously demonstrated that cerebrospinal fluid-derived B cells from early relapsing–remitting multiple sclerosis (RRMS) patients that express a VH4 gene accumulate specific replacement mutations. These mutations can be quantified as a score that identifies such patients as having or likely to convert to RRMS. Furthermore, we showed that next generation sequencing is an efficient method for obtaining the sequencing information required by this mutation scoring tool, originally developed using the less clinically viable single-cell Sanger sequencing. Objective To determine the accuracy of MSPrecise, the diagnostic test that identifies the presence of the RRMS-enriched mutation pattern from patient cerebrospinal fluid B cells. Methods Cerebrospinal fluid cell pellets were obtained from RRMS and other neurological disease (OND) patient cohorts. VH4 gene segments were amplified, sequenced by next generation sequencing and analyzed for mutation score. Results The diagnostic test showed a sensitivity of 75% on the RRMS cohort and a specificity of 88% on the OND cohort. The accuracy of the test in identifying RRMS patients or patients that will develop RRMS is 84%. Conclusion MSPrecise exhibits good performance in identifying patients with RRMS irrespective of time with RRMS.

Objective The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22). Methods Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months. Results rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0–Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort. Conclusions Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Background: Debate exists about whether neuromyelitis optica spectrum disorder seronegative disease represents the same immune-mediated attack on astrocytic aquaporin-4 as in seropositive disease. Objective: We investigated whether response to common treatments for neuromyelitis optica spectrum disorder differed by serostatus, as assessed by change in annualized relapse rate. Methods: We performed a multicenter retrospective analysis of 245 patients with neuromyelitis optica spectrum disorder who were treated with either rituximab or mycophenolate mofetil as their first-line immunosuppressive treatment for disease prevention. Patients were followed for a minimum of 6 months following treatment initiation. Results: In those started on rituximab, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.81 and 1.93, respectively. On-treatment annualized relapse rates significantly declined to 0.32 (seropositive; p Conclusion: In this international collaboration involving a large number of neuromyelitis optica spectrum disorder patients, treatment was effective regardless of serostatus. This suggests that treatment should not differ when considering these treatments.

Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade.To examine potential environmental factors in pediatric MS using geographic information systems (GIS).Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects' geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence20 or ≥20 miles from the recruiting center), using logistic regression.Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.9020 miles from center; p = 0.43 ≥ 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside ≥ 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3).Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

Immune-mediated central nervous system (CNS) demyelinating diseases impact various areas of the brain, optic nerves, and/or spinal cord and can result in a wide range of neurologic symptoms including adverse cognitive outcomes. Neuropsychological outcomes in adult multiple sclerosis (MS) are well documented, while literature on such outcomes in pediatric cohorts is more limited. Furthermore, literature on neuropsychological outcomes in pediatric acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and transverse myelitis (TM) is even more limited. This paper is the first to review what is known about neuropsychological outcomes associated with immune-mediated CNS demyelinating diseases, with a focus on pediatric MS, ADEM, NMO, and TM. Additionally, this review illuminates the need to clarify differences in neuropsychological sequelae between conditions, characterize longitudinal cognitive outcomes, and investigate neuropsychological outcomes in relation to clinical variables (e.g., age of onset, disease duration, number of relapses) and psychosocial variables (e.g., fatigue, emotional problems, behavioral functioning) to better understand neuropsychological outcomes associated with these conditions.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27-, CD45RO-) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS.

Low-contrast letter acuity and optical coherence tomography (OCT) capture visual dysfunction and axonal loss in adult-onset multiple sclerosis (MS), and have been proposed as secondary outcome metrics for therapeutic trials. Clinical trials will soon be launched in pediatric MS, but such outcome metrics have not been well-validated in this population.To determine whether MS onset during childhood and adolescence is associated with measurable loss of visual acuity and thinning of the retinal nerve fiber layer (RNFL), whether such features are noted only in the context of clinical optic nerve inflammation (optic neuritis, ON) or are a feature of MS even in the absence of optic nerve relapses, and to define the optimal methods for such detection.Cross-sectional study.Monocular and binocular high- and low-contrast letter acuity and contrast sensitivity were assessed in a cross-sectional cohort of children (ages 5 to 17 years) with MS (N=22 patients, 44 eyes; 8 patients with a history of ON) and disease-free controls (N=29 patients; 58 eyes) from three academic centers. Binocular summation was determined by calculating the number of letters correctly identified using the binocular score minus the better eye score for each visual test. RNFL thickness was measured using OCT (Stratus OCT-3). Results were analyzed in terms of "eyes" as: MS ON+, MS ON-, and control eyes. Generalized estimating equation (GEE) regression models were used to compare patients to controls.Traditional high-contrast visual acuity scores did not differ between MS ON+, MS ON-, and controls eyes. MS ON+ eyes had decreased monocular (p0.001) and decreased binocular (p=0.007) low-contrast letter acuity (Sloan 1.25% contrast charts) scores. Monocular visual acuity did not differ when comparing MS ON- and control eyes. The magnitude of binocular summation using low-contrast charts was similar for pediatric MS participants and controls and was not diminished in children with a history of ON. While the mean RNFL thickness for all MS eyes (103±17 μm) trended lower when compared to corresponding measures in control eyes (109±9 μm,Low-contrast letter acuity detects subtle visual loss in MS patients with prior ON, consistent with incomplete recovery, a finding further supported by RNFL loss in ON affected eyes. In MS patients with prior unilateral ON, binocular acuity is decreased; however, the magnitude of binocular summation is preserved, unlike adult-onset MS who exhibit a reduced capacity for visual compensation in the context of unilateral injury. Also unlike findings in adult-onset MS, we did not demonstrate RNFL thinning in ON- eyes of children and adolescents with MS. Further validation is required to confirm whether neurodegeneration of visual pathways occurs in the absence of relapse, and thus whether OCT will serve as a sensitive metric for such pathology in the pediatric and adolescent MS context.

Summary During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk–benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.