Assessing Needs and Perceptions of Research Participation in Pediatric-Onset Multiple Sclerosis: A Multistakeholder Survey.

BACKGROUND: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey. METHODS: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS). RESULTS: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs. CONCLUSIONS: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation.

Neurologic involvement in seronegative primary Sjögren's syndrome with positive minor salivary gland biopsy: a single-center experience.

Objective: To assess the demographics, neurologic manifestations, comorbidities, and treatment of patients with seronegative primary Sjögren's syndrome (pSS). Patients and methods: We conducted a retrospective chart review on patients with seronegative pSS evaluated by a neurologist at the University of Utah Health between January 2010 and October 2018. The diagnosis was based on characteristic symptoms, positive minor salivary gland biopsy according to the American-European Consensus Group 2002 criteria, and seronegative antibody status. Results: Of 45 patients who met the study criteria, 42 (93.3%) were Caucasian, and 38 (84.4%) were female. The patients' mean age at diagnosis was 47.8 ± 12.6 (range 13-71) years. Paresthesia, numbness and dizziness, and headache were noted in 40 (88.9%), 39 (86.7%), and 36 patients (80.0%), respectively. Thirty-four patients underwent brain magnetic resonance imaging. Of these, 18 (52.9%) showed scattered nonspecific periventricular and subcortical cerebral white matter T2/fluid-attenuated inversion recovery hyperintense foci. Twenty-nine patients (64.4%) presented to the neurology clinic prior to pSS diagnosis, and the median delay in diagnosis from the first neurology clinic visit was 5 (interquartile ranges 2.0-20.5) months. Migraine and depression were the most common comorbidities in 31 patients (68.9%). Thirty-six patients received at least one immunotherapy, and 39 were on at least one medication for neuropathic pain. Conclusion: Patients often display various nonspecific neurological symptoms. Clinicians should express a high degree of skepticism regarding seronegative pSS and consider minor salivary gland biopsy to avoid delaying diagnosis, as undertreatment can affect patients' quality of life.

Clinical and epidemiological correlates of treatment change in patients with NMOSD: insights from the CIRCLES cohort.

OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) represent rare autoimmune diseases of the central nervous system largely targeting optic nerve(s) and spinal cord. The present analysis used real-world data to identify clinical and epidemiological correlates of treatment change in patients with NMOSD. METHODS: CIRCLES is a longitudinal, observational study of NMOSD conducted at 15 centers across North America. Patients with ≥ 60 days of follow-up and receiving on-study maintenance treatment were evaluated. The mean annual relapse rate (ARR) was estimated using negative binomial models; the likelihood of treatment change was estimated using Cox proportional hazards models. Relapses were included as time-varying covariates to estimate the relationship to treatment change. RESULTS: Of 542 patients included, 171 (31.5%) experienced ≥ 1 relapse on the study and 133 patients (24.5%) had ≥ 1 change in the treatment regimen. Two categories of variables significantly correlated with the likelihood of treatment change: (1) relapse: any on-study relapse (hazard ratio [HR] = 2.91; p < 0.001), relapse phenotypes (HR range = 2.15-5.49; p < 0.001), and pre-study ARR > 0.75 (HR 2.28; p < 0.001); 2) disease phenotype: brain syndrome only vs transverse myelitis involvement at onset (HR 2.44; p = 0.008), disease duration < 1 vs > 5 years (HR 1.66; p = 0.028), or autoimmune comorbidity (HR 1.55; p = 0.015). A subset of these factors significantly correlated with shorter time to first rituximab discontinuation. CONCLUSIONS: In CIRCLES, relapse patterns and disease phenotype significantly correlated with changes in the maintenance treatment regimen. Such findings may facilitate the identification of patients with NMOSD who are likely to benefit from treatment change to reduce relapse risk or disease burden and enhance the quality of life.

Aquaporin-4 Autoantibody Detection by ELISA: A Retrospective Characterization of a Commonly Used Assay.

OBJECTIVE: Aquaporin-4 (AQP4) serum autoantibodies are detected by a variety of methods. The highest sensitivity is achieved with cell-based assays, but the enzyme-linked immunosorbent assay (ELISA) is still commonly utilized by clinicians worldwide. METHODS: We performed a retrospective review to identify all patients at the University of Utah who had AQP4 ELISA testing at ARUP Laboratories from 2010 to 2017. We then reviewed their diagnostic evaluation and final diagnosis based on the ELISA titer result. RESULTS: A total of 750 tests for the AQP4 ELISA were analyzed, and 47 unique patients with positive titers were identified. Less than half of these patients (49%) met the clinical criteria for neuromyelitis optica spectrum disorder (NMOSD). In cases of low positive titers (3.0-7.9 U/mL, n = 19), the most common final diagnosis was multiple sclerosis (52.6%). In the moderate positive cohort (8.0-79.9 U/mL, n = 14), only a little more than half the cohort (64.3%) had NMOSD. In cases with high positives (80-160 U/mL, n = 14), 100% of patients met clinical criteria for NMOSD. CONCLUSIONS: Our data illustrates diagnostic uncertainty associated with the AQP4 ELISA, an assay that is still commonly ordered by clinicians despite the availability of more sensitive and specific tests to detect AQP4 autoantibodies in patients suspected of having NMOSD. In particular, low positive titer AQP4 ELISA results are particularly nonspecific for the diagnosis of NMOSD. The importance of accessibility to both sensitive and specific AQP4 testing cannot be overemphasized in clinical practice.

Modern Look at Transverse Myelitis and Inflammatory Myelopathy: Epidemiology of the National Veterans Health Administration Population.

BACKGROUND AND OBJECTIVES: To characterize population-level data associated with transverse myelitis (TM) within the US Veterans Health Administration (VHA). METHODS: This retrospective review used VHA electronic medical record from 1999 to 2015. We analyzed prevalence, disease characteristics, modified Rankin Scale (mRS) scores, and mortality data in patients with TM based on the 2002 Diagnostic Criteria. RESULTS: We identified 4,084 patients with an International Classification of Diseases (ICD) code consistent with TM and confirmed the diagnosis in 1,001 individuals (90.7% males, median age 64.2, 67.7% Caucasian, and 31.4% smokers). The point prevalence was 7.86 cases per 100,000 people. Less than half of the cohort underwent a lumbar puncture, whereas only 31.8% had a final, disease-associated TM diagnosis. The median mRS score at symptom onset was 3 (interquartile range 2-4), which remained unchanged at follow-up, although less than half (43.2%) of the patients received corticosteroids, IVIg, or plasma exchange. Approximately one-quarter of patients (24.3%) had longitudinal extensive TM, which was associated with poorer outcomes (p = 0.002). A total of 108 patients (10.8%) died during our review (94.4% males, median age 66.5%, and 70.4% Caucasian). Mortality was associated with a higher mRS score at follow-up (OR 1.94, 95% CI, 1.57-2.40) and tobacco use (OR 1.87, 95% CI, 1.17-2.99). DISCUSSION: This national TM review highlights the relatively high prevalence of TM in a modern cohort. It also underscores the importance of a precise and thorough workup in this disabling disorder to ensure diagnostic precision and ensure optimal management for patients with TM in the future.

Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: The 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. METHODS: Data 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. RESULTS: There 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 < 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. DISCUSSION: The 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.

Biopsy-proven PML in an HIV-negative patient with discoid lupus: Failure to detect JC virus in CSF.

We present a case of a 58-year-old man with a history of severe discoid lupus erythematosus and acute encephalopathy and incoordination. Antinuclear antibody testing was weakly positive but all other laboratory tests for systemic lupus erythematosus were negative and serum quantitative immunoglobulins and lymphocytes were normal. MRI brain showed T2/FLAIR hyperintensities within the bilateral parietal and temporal lobes with involvement of subcortical U fibers. CSF PCR was negative for varicella-zoster virus, herpes simplex, JCV and BK virus. However, JCV antibody index was elevated (3.88; reference: < 0.2). Right parietal brain biopsy was consistent with JCV infection and diagnostic of progressive multifocal leukoencephalopathy (PML). To the best of our knowledge, this is the first reported case of PML in a patient with discoid lupus without other traditional risk factors for the disease and highlights the need for clinical vigilance in this patient population.

High-b diffusivity of MS lesions in cervical spinal cord using ultrahigh-b DWI (UHb-DWI).

PURPOSE: The purpose of this study was to investigate UHb-rDWI signal in white matter tracts of the cervical spinal cord (CSC) and compare quantitative values between healthy control WM with both MS NAWM and MS WM lesions. METHODS: UHb-rDWI experiments were performed on (a) 7 MS patients with recently active or chronic lesions in CSC and on (b) 7 healthy control of similar age range and gender distribution to MS subjects. All MRI data were acquired using clinical 3T MRI system. Axial high-b diffusion images were acquired using 2D single-shot DW stimulated EPI with reduced FOV and a CSC-dedicated 8 channel array coil. High-b diffusion coefficient DH was estimated by fitting the signal-b curve to a double or single-exponential function. RESULTS: The high-b diffusivity DH values were measured as (0.767 ± 0.297) × 10-3 mm2/s in the posterior column lesions, averaged over 6 MS patients, and 0.587 × 10-3 mm2/s in the corticospinal tract for another patient. The averaged DH values of the 7 healthy volunteers from the posterior and lateral column were (0.0312 ± 0.0306) × 10-3 and (0.0505 ± 0.0205) × 10-3 mm2/s, respectively. UHb-rDWI signal-b curves of the MS patients revealed to noticeably behave differently to that of the healthy controls. The patient signal-b curves decayed with greater high-b decay constants to reach lower signal intensities relative to signal-b curves of the healthy controls. CONCLUSION: UHb-DWI of the CSC reveals a marked difference in signal-b-curves and DH values in MS lesions compared to NAWM and healthy control WM. Based on physical principles, we interpret these altered observations of quantitative diffusion values to be indicative of demyelination. Further studies in animal models will be required to fully interpret UHb-DWI quantitative diffusion values during demyelination and remyelination.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Consistent efficacy of daclizumab beta across patient demographic and disease activity subgroups in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a. OBJECTIVES: To determine if the efficacy of daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. METHODS: In the SELECT study, patients received daclizumab beta 150 or 300mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab beta 150mg administered subcutaneously every 4 weeks for 96-144 weeks, and were compared with patients who received IM interferon beta-1a 30µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use. RESULTS: Treatment with daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). CONCLUSIONS: These findings suggest that treatment with daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.

Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis.

Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56-bright natural killer cells. Intravenous daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.

Two-dimensional single-shot diffusion-weighted stimulated EPI with reduced FOV for ultrahigh-b radial diffusion-weighted imaging of spinal cord.

PURPOSE: High-resolution diffusion-weighted imaging (DWI) of the spinal cord (SC) is problematic because of the small cross-section of the SC and the large field inhomogeneity. Obtaining the ultrahigh-b DWI poses a further challenge. The purpose of the study was to design and validate two-dimensional (2D) single-shot diffusion-weighted stimulated echo planar imaging with reduced field of view (2D ss-DWSTEPI-rFOV) for ultrahigh-b radial DWI (UHB-rDWI) of the SC. METHODS: A novel time-efficient 2D ss-DWSTEPI-rFOV sequence was developed based on the stimulated echo sequence. Reduced-phase field of view was obtained by using two slice-selective 90 ° radiofrequency pulses in the presence of the orthogonal slice selection gradients. The sequence was validated on a cylindrical phantom and demonstrated on SC imaging. RESULTS: Ultrahigh-b radial diffusion-weighted ( bmax = 7300 s/mm2) images of the SC with greatly reduced distortion were obtained. The exponential plus constant fitting of the diffusion-decay curve estimated the constant fraction (restricted water fraction) as 0.36 ± 0.05 in the SC white matter. CONCLUSION: A novel 2D ss-DWSTEPI-rFOV sequence has been designed and demonstrated for high-resolution UHB-rDWI of localized anatomic structures with significantly reduced distortion induced by nonlinear static field inhomogeneity. Magn Reson Med 77:2167-2173, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Characterization of spinal cord white matter by suppressing signal from hindered space. A Monte Carlo simulation and an ex vivo ultrahigh-b diffusion-weighted imaging study.

Signal measured from white matter in diffusion-weighted imaging is difficult to interpret because of the heterogeneous structure of white matter. Characterization of the white matter will be straightforward if the signal contributed from the hindered space is suppressed and purely restricted signal is analyzed. In this study, a Monte Carlo simulation (MCS) of water diffusion in white matter was performed to understand the behavior of the diffusion-weighted signal in white matter. The signal originating from the hindered space of an excised pig cervical spinal cord white matter was suppressed using the ultrahigh-b radial diffusion-weighted imaging. A light microscopy image of a section of white matter was obtained from the excised pig cervical spinal cord for the MCS. The radial diffusion-weighted signals originating from each of the intra-axonal, extra-axonal, and total spaces were studied using the MCS. The MCS predicted that the radial diffusion-weighted signal remains almost constant in the intra-axonal space and decreases gradually to about 2% of its initial value in the extra-axonal space when the b-value is increased to 30,000s/mm2. The MCS also revealed that the diffusion-weighted signal for a b-value greater than 20,000s/mm2 is mostly from the intra-axonal space. The decaying behavior of the signal-b curve obtained from ultrahigh-b diffusion-weighted imaging (bmax∼30,000s/mm2) of the excised pig cord was very similar to the decaying behavior of the total signal-b curve synthesized in the MCS. A mono-exponential plus constant fitting of the signal-b curve obtained from a white matter pixel estimated the values of constant fraction and apparent diffusion coefficient of decaying fraction as 0.32±0.05 and (0.16±0.01)×10-3mm2/s, respectively, which agreed well with the results of the MCS. The signal measured in the ultrahigh-b region (b>20,000s/mm2) is mostly from the restricted (intra-axonal) space. Integrity and intactness of the axons can be evaluated by assessing the remaining signal in the ultrahigh-b region.

Characteristics of Children and Adolescents With Multiple Sclerosis.

OBJECTIVES: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States. METHODS: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers. RESULTS: A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age. CONCLUSIONS: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children.

Clinical features of neuromyelitis optica in children: US Network of Pediatric MS Centers report.

OBJECTIVE: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases. METHODS: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified. RESULTS: Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS. CONCLUSION: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.

The role of the prostaglandin E2 receptors in vulnerability of oligodendrocyte precursor cells to death.

BACKGROUND: Activity of cyclooxygenase 2 (COX-2) in mouse oligodendrocyte precursor cells (OPCs) modulates vulnerability to excitotoxic challenge. The mechanism by which COX-2 renders OPCs more sensitive to excitotoxicity is not known. In the present study, we examined the hypothesis that OPC excitotoxic death is augmented by COX-2-generated prostaglandin E2 (PGE2) acting on specific prostanoid receptors which could contribute to OPC death. METHODS: Dispersed OPC cultures prepared from mice brains were examined for expression of PGE2 receptors and the ability to generate PGE2 following activation of glutamate receptors with kainic acid (KA). OPC death in cultures was induced by either KA, 3'-O-(Benzoyl) benzoyl ATP (BzATP) (which stimulates the purinergic receptor P2X7), or TNFα, and the effects of EP3 receptor agonists and antagonists on OPC viability were examined. RESULTS: Stimulation of OPC cultures with KA resulted in nearly a twofold increase in PGE2. OPCs expressed all four PGE receptors (EP1-EP4) as indicated by immunofluorescence and Western blot analyses; however, EP3 was the most abundantly expressed. The EP3 receptor was identified as a candidate contributing to OPC excitotoxic death based on pharmacological evidence. Treatment of OPCs with an EP1/EP3 agonist 17 phenyl-trinor PGE2 reversed protection from a COX-2 inhibitor while inhibition of EP3 receptor protected OPCs from excitotoxicity. Inhibition with an EP1 antagonist had no effect on OPC excitotoxic death. Moreover, inhibition of EP3 was protective against toxic stimulation with KA, BzATP, or TNFα. CONCLUSION: Therefore, inhibitors of the EP3 receptor appear to enhance survival of OPCs following toxic challenge and may help facilitate remyelination.

The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps.

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network.

Retinal nerve fiber layer sector-specific compromise in relapsing and remitting multiple sclerosis.

OBJECTIVE: To evaluate quadrant and sector retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) in relapsing-remitting multiple sclerosis (RR-MS) patients. METHODS: Optical coherence tomography measures of RNFL and TMV were studied in 321 eyes without prior optic neuritis (ON) (MS unaffected), 151 eyes with prior ON (MS affected), and 148 healthy control eyes. RESULTS: Mean RNFL thickness was significantly lower in the MS affected and MS unaffected groups relative to the control group (p < 0.0001). RNFL thicknesses in the superior, inferior, and temporal quadrants were significantly reduced in MS unaffected (113 ± 15 µm, 119 ± 17 µm, 63 ± 13 µm) (p < 0.001) and MS affected groups (99 ± 19 µm, 103 ± 21 µm, 51 ± 13 µm) (p < 0.0001) compared with that in controls (120 ± 14 µm, 128 ± 15 µm, 69 ± 8 µm, respectively). TMV was significantly reduced in both the MS affected and MS unaffected groups compared with that in the controls (p < 0.0001). CONCLUSION: Quadrant, sector, and PMB RNFL thicknesses are significant individual measures in RR-MS for both affected and unaffected eyes and may prove valuable in future investigations including biomarker and outcomes research.

Protective environmental factors for neuromyelitis optica.

OBJECTIVE: To determine whether early environmental factors, such as cesarean delivery, breastfeeding, and exposure to smoking or herpes viruses, are associated with neuromyelitis optica (NMO) risk in children. METHODS: This is a case-control study of pediatric NMO, multiple sclerosis (MS), and healthy subjects. Early-life exposures were obtained by standardized questionnaire. Epstein-Barr virus, cytomegalovirus, and herpes simplex virus 1 antibody responses were determined by ELISA. Multivariate logistic regression models were used to adjust for age at sampling, sex, race, and ethnicity. RESULTS: Early-life exposures were obtained from 36 pediatric subjects with NMO, 491 with MS, and 224 healthy controls. Daycare (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.14, 0.78; p < 0.01) and breastfeeding (OR 0.42, 95% CI 0.18, 0.99; p = 0.05) were associated with lower odds of having NMO compared with healthy subjects. Cesarean delivery tended to be associated with 2-fold-higher odds of NMO compared with having MS/clinically isolated syndrome (OR 1.98, 95% CI 0.88, 4.59; p = 0.12) or with being healthy (OR 1.95, 95% CI 0.81, 4.71; p = 0.14). Sera and DNA were available for 31 subjects with NMO, 189 with MS, and 94 healthy controls. Epstein-Barr virus, herpes simplex virus 1, cytomegalovirus exposure, and being HLA-DRB1*15 positive were not associated with odds of having NMO compared with healthy subjects. CONCLUSIONS: Exposure to other young children may be an early protective factor against the development of NMO, as previously reported for MS, consistent with the hypothesis that infections contribute to disease risk modification. Unlike MS, pediatric NMO does not appear to be associated with exposures to common herpes viruses.