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Summary Purpose The 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard. Methods We identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty-two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re-reviewed with neuropathologists, and MRI imaging was re-reviewed with a neuroradiologist. Key Findings RE was considered in the differential diagnosis for 82 patients, of whom 35 had biopsies. Twenty patients met full criteria (positive) without another explanation, including seven for whom biopsy was required to meet criteria and one in whom another etiology was identified. Two patients met full criteria but had another explanation. Thirty-five met partial criteria (negative), of whom 14 had another etiology identified. Twenty-five met no criteria (negative). The diagnostic criteria had a sensitivity of 81% with four false negatives (criteria-negative, biopsy-positive) when compared to pathology as a gold standard. Five false positives (criteria positive, biopsy negative) had identifiable alternate diagnoses. Significance The 2005 Bien clinical diagnostic criteria for RE have reasonably high sensitivity and specificity and good clinical-pathologic correlation in most cases. We suggest modification of the criteria to allow inclusion of cases with well-described but less common features. Specifically we suggest making the diagnosis in the absence of epilepsia partialis continua (EPC) or clear progression of focal cortical deficits or MRI findings if biopsy is positive and two of the A criteria are met (B3 plus two of three A criteria). This would improve the sensitivity of the criteria.

Studies of the underlying immune mechanisms of multiple sclerosis (MS) in children may shed light on the initial events of MS pathogenesis. We studied T cell responses to myelin peptides in 10 pediatric MS patients (PMS), 10 pediatric healthy controls (PHC), 10 adult MS patients (AMS) and 10 adult healthy controls (AHC). A significantly higher proportion of divided CD4+ T cell responses in response to myelin peptides by the CFSE assay in PMS compared to PHC at both concentrations of myelin peptide tested (t test, 95% CI, p=0.0067 for MP1; p=0.0086 for MP10), and between PMS and AMS (p=0.0012 at 1 μg/mL of myelin peptides, p0.0001 at 10 μg/mL) was found. In addition, T cells with a central memory phenotype producing IL-17 were increased in PMS compared to PHC (p0.05). IL-7 levels in culture supernatants were elevated in PMS compared to PHC and AMS (t test0.01).

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 10 6 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed ( p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 10 6 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses.

BACKGROUND AND PURPOSE: DTI has shown focal and diffuse white matter abnormalities in adults and children with MS. Here we explore whether DTI abnormalities are present at the time of a first attack or CIS in children and whether early DTI features can predict the development of MS. MATERIALS AND METHODS: We assessed region-of-interest and tract-based mean ADC and mean FA values for 3 major white matter pathways and NAWM in 20 children with MS, 27 children with forms of CIS, and controls. Tracts were selected by using standard region-of-interest placements on color FA maps. Identical ROIs were placed in the NAWM on b = 0 T2-weighted images to ensure that both ROIs and resulting tracts passed through NAWM. Conventional MR imaging characteristics were assessed by visual inspection. Statistical analysis compared FA and ADC values between groups by a t test. Logistic regression assessed the predictive value of DTI measures and published conventional MR imaging measures for conversion from CIS to MS. RESULTS: In pediatric patients with MS, all white matter pathways and analysis confined to the NAWM demonstrated higher mean ADC values and lower mean FA than in controls. In contrast, there were no significant differences in mean ADC and mean FA of white matter pathways in all CIS cohorts compared with controls. In the CIS cohort, none of the DTI measures in white matter pathways or in NAWM were significantly associated with conversion to RRMS in univariate or multivariate models (P > .05 in all models). CONCLUSIONS: There are significant anisotropic abnormalities in the NAWM of major tracts in children with MS. In contrast, there were no significant changes in pediatric patients with CIS compared with controls at baseline. DTI measures did not predict conversion to MS. The period between CIS and conversion to pediatric MS may represent a window of opportunity for the prevention of diffuse damage in the CNS and potentially progressive disability.

Distal partial trisomies involving the region 1q32 have been associated with dysmorphic features and developmental delay [1-11]. To further define the critical region for developmental delay and to investigate the genotype-phenotype association of 1q trisomy syndrome, we report two patients with much smaller (3 Mb and 3.5 Mb in size) trisomic regions on 1q32.1. The two micro-duplications largely overlap and both patients exhibited cognitive and motor delays. Case 1 is a 5-year-old boy with global developmental delay, behavioral problems, pervasive developmental disorder not otherwise specified (PDD-NOS), staring spells, headaches, and paresthesias. Case 2 is a 14-year-old girl with seizures, cognitive and motor difficulties, and minor dysmorphic features. These two cases suggest that 1q32.1 region on distal arm of 1q and genes involved are critical to cognitive and motor development in a gene dosage sensitive manner and that other neurological features are variable within this syndrome.

Importance Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based onzscores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weightedzscore was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans,Aspergillus oryzae,Histoplasma capsulatum, andCandida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weightedzscore–based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused byAspergillus oryzae, and the fourth reported case ofC dubliniensismeningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

A radioimmunoassay (RIA) to detect antibodies against what was initially believed to be voltage-gated potassium channels (VGKC) in patients with neuromyotonia was established 20 years ago.1 The rationale for this test came from previous RIA assays that detected antibodies against acetylcholine receptors or voltage-gated calcium channels in which the antigens were labeled with 125I-specific neurotoxins and precipitated with patients' antibodies.1 It was soon clear that the results of the VGKC RIA were very different from those expected based on the achievements of the RIA for the antibodies associated with myasthenia gravis and the Lambert-Eaton syndrome. First, only a minority of patients with neuromyotonia, the initial disease target of the VGKC RIA, were positive. Second, high levels of VGKC antibodies were found in a subset of patients with nonparaneoplastic limbic encephalitis and good response to immunotherapy.2 Third, it was known by 2004 that low levels of VGKC antibodies occurred in 5% of subjects without neurologic disorders.2 However, no recommendations on the clinical value, if any, of these low-positive VGKC antibody levels were provided until a decade later.3,4 Finally, as the VGKC RIA test became more widely available, the type of clinical syndromes reportedly associated with these antibodies increased exponentially in both adults and children.3–5

We describe two siblings with neonatal hypocalcemic seizures whose mother took topiramate during both pregnancies. Apart from hypocalcemia, the patients had no identifiable etiology for their seizures. Although biochemical data suggested that the hypocalcemia was caused by hypoparathyroidism, no disorders typically associated with this condition were identified in the patients. We propose that topiramate exposure in utero led to hypoparathyroidism and subsequent hypocalcemia via effects on protein kinase A signaling, resulting in hypocalcemic seizures. Neonates exposed to topiramate in utero should be monitored for hypocalcemic seizures.

Although individually uncommon, infectious, inflammatory, and autoimmune conditions collectively comprise an important subset of acute pediatric neurology. In this chapter, we discuss encephalitis, transverse myelitis, and optic neuritis. We discuss both a general initial approach to diagnosis and management prior to a specific diagnosis being made, as well as characteristic features of some of the most important entities, including herpes simplex virus encephalitis, enterovirus encephalitis, Lyme disease, acute disseminated encephalomyelitis, transverse myelitis, and optic neuritis.

Objective To compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease. Methods Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Women's Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval. Results ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1–5 did not impact year 5 disability measured by EDSS in POMS. Conclusions Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.

Background Daclizumab, a humanized monoclonal antibody specific for the interleukin 2 receptor α chain, reduces clinical and magnetic resonance imaging disease activity in patients with adult-onset multiple sclerosis (MS) as monotherapy or add-on therapy with interferon. Objective To report the use of daclizumab in pediatric-onset MS. Design Case series. Setting Two comprehensive pediatric MS centers. Patients Seven patients with pediatric-onset MS with clinical and magnetic resonance imaging disease activity despite first-line disease-modifying therapy. Intervention Intravenous daclizumab, 1 mg/kg monthly. Main Outcome Measures Annualized relapse rates, Expanded Disability Status Scale scores, contrast-enhancing lesions, and adverse effects. Results Treatment with daclizumab, primarily combined with interferon, was associated with reductions in annualized relapse rates and contrast-enhancing lesions and with reduction or stabilization of Expanded Disability Status Scale scores in each patient. However, 4 patients had relapses and new contrast-enhancing lesions during daclizumab treatment. No significant adverse effects occurred. Conclusion Daclizumab may be a safe and at least partially effective treatment option for patients with pediatric-onset MS with disease activity despite first-line disease-modifying therapy.

In this issue of Neurology ®, Aubert-Broche et al.1 study the longitudinal change in brain volume in 36 children with multiple sclerosis (MS) (mean age at scan 13.77 years) compared to 25 local healthy children and 339 healthy children from an NIH-sponsored database. This is the first study to compare the trajectory of brain growth in pediatric MS compared to normative controls. The same 1.5T MRI protocol was utilized for all study groups, and the preprocessed T1-weighted images of each time point were linearly coregistered to a subject-specific linear template. Mixed effect models, adjusting for age and sex, were used to estimate and compare growth trajectories. The major findings in the study were that brain volumes were lower in children with MS compared to healthy children of comparable age, and that, in children with MS, there was a downward trajectory in brain volume compared to the growth observed in healthy children. This downward trajectory in brain volume in the patients with MS was due to both a failure of age-expected brain growth as well as subsequent and progressive atrophy. These findings may differ from those of adult patients with MS in whom we assume that the brain is fully developed, and then atrophy ensues; however, this assumption needs to be tested through comparative studies. Deep gray matter structure volumetrics, adjusted for whole brain volume, showed lesser thalamic growth and marginal changes in the globus pallidus, compared to no change in the caudate and putamen. Higher T2 lesion load was associated with smaller thalamic volumes longitudinally. The main limitation of this study is the small number of patients assessed.

Opsoclonus-myoclonus-ataxia syndrome (OMS) is a severe autoimmune central nervous system disorder, which predominantly affects young children and causes lifelong neurological disability. Early recognition and treatment may yield better outcomes.Appreciation of the spectrum of clinical presentations of OMS, awareness of common misdiagnoses, and utilization of diagnostic criteria may facilitate the timely diagnosis of OMS. Approximately 50% of patients have an associated neuroblastoma, which may escape detection by traditional methods and require MRI or computed tomography of the torso for diagnosis. In nonparaneoplastic cases, many associated infections have been reported. Although there has been progress in autoantibody identification and cerebrospinal fluid B cell expansion is a common finding, there is no diagnostic biomarker for OMS currently. Approximately 80% of reported patients, typically treated with conventional therapies such as adrenocorticotropin hormone, corticosteroids, and/or intravenous immunoglobulin, develop long-term neurological morbidity. Newer treatment approaches using early, aggressive therapy with cyclophosphamide or rituximab are promising.The diagnosis of OMS requires a high level of suspicion and a systematic approach for diagnostic testing, particularly for neuroblastoma. Future collaborative studies are required to determine whether early, aggressive therapy will improve the typically poor long-term neurological outcome.

The clinical and MRI presentation differs between earlier- and later-onset pediatric multiple sclerosis (MS), whereas the effect of age on the CSF inflammatory profile is unknown and may contribute to delayed diagnosis.To compare the CSF cellular and immunoglobulin G (IgG) profiles between earlier- and later-onset pediatric MS.We queried the databases of 6 pediatric MS centers for earlier-onset (onset11 years) and later-onset (or = 11 and18 years) patients with MS or clinically isolated syndrome who underwent CSF analysis within the first 3 months of presentation (observational study). We compared CSF white blood cell (WBC) differential count, IgG index, and IgG oligoclonal bands between age groups.We identified 40 earlier-onset (mean age at onset = 7.2 +/- 2.7 years, 60% females) and 67 later-onset pediatric MS patients (15.1 +/- 1.7 years, 63% females). Although WBC count tended to be higher in earlier-onset patients (median = 9/mm(3) [0-343] vs 6 [0-140], p = 0.15), they had a lower proportion of lymphocytes (70% [0-100] vs 93% [0-100] of WBCs, p = 0.0085; difference = +3% per 1-year increase of age, p = 0.0011) and higher proportion of neutrophils than later-onset patients (0.5% [0-75] vs 0% [0-50] of WBCs, p = 0.16; difference = -1% per 1-year increase of age, p = 0.033). In earlier-onset disease, fewer patients had an elevated IgG index than in the later-onset group (35% vs 68% of patients, p = 0.031).Age modifies the CSF profile at pediatric multiple sclerosis (MS) onset, which may mislead the diagnosis. Our findings suggest an activation of the innate rather than the adaptive immune system in the earlier stages of MS or an immature immune response.

Objective: To review our multicenter experience with cyclophosphamide in the treatment of children with multiple sclerosis (MS). Methods: Retrospective chart review of children with MS treated with cyclophosphamide. Demographic, clinical, treatment, and MRI parameters were collected. Results: We identified 17 children with MS treated with cyclophosphamide. All but one had worsening of Expanded Disability Status Scale scores or multiple relapses prior to treatment initiation. Children were treated with one of three regimens: 1) induction therapy alone; 2) induction therapy with pulse maintenance therapy; or 3) pulse maintenance therapy alone. Treatment resulted in a reduction in relapse rate and stabilization of disability scores assessed 1 year after treatment initiation in the majority of patients. Longer follow-up was available for most cases. Cyclophosphamide was well tolerated in most patients. However, side effects included vomiting, transient alopecia, osteoporosis, and amenorrhea. One patient developed bladder carcinoma that was successfully treated. Conclusions: Cyclophosphamide is an option for the treatment of children with aggressive multiple sclerosis refractory to first-line therapies. Recommendations regarding patient selection, treatment administration, and monitoring are discussed.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

To investigate whether or not the disparity in disease progression in those with pediatric-onset compared with adult-onset multiple sclerosis (MS) is due to differences in relapse rates.Inception cohort. Mean follow-up times were 3.67 (standard deviation, 1.64) and 3.98 (standard deviation, 1.17) years in the pediatric and adult groups, respectively.Comprehensive MS centers.Patients with relapsing-remitting MS who were seen at the pediatric and adult MS centers at Massachusetts General and Brigham and Women's Hospitals, respectively, 12 months or less from onset of first symptom in July 2001 or later and were followed up for 12 months or longer. One hundred ten patients with adult-onset and 21 patients with pediatric-onset MS were included. Three eligible patients with adult-onset MS were excluded owing to incomplete records.Annualized relapse rates were compared between pediatric-onset and adult-onset patients using the proportional means model.The annualized relapse rate in the pediatric-onset group was significantly higher than that in the adult-onset group (1.13 vs 0.40; P.001) with an adjusted rate ratio of 2.81 (95% confidence interval, 2.07-3.81). When we controlled for time spent undergoing disease-modifying treatment in the analysis, the difference between the groups remained highly significant (adjusted rate ratio, 2.82; 95% confidence interval, 2.08-3.83; P.001). When age at disease onset was treated as a continuous variable, a highly significant association between age and relapse rate was observed (P.001).Relapses are more frequent in patients with pediatric-onset compared with adult-onset MS in the disease-modifying treatment era. This finding suggests that patients with pediatric-onset MS experience a more inflammatory disease course than patients with adult onset of the disease.

We describe a 14-year-old boy with acute transverse myelitis after breakthrough varicella infection, despite immunization with the Varicella zoster virus vaccine 8 years earlier. He recovered fully after treatment with intravenous corticosteroids and acyclovir. To our knowledge, there are no previously reported cases of postvaricella acute transverse myelitis in vaccinated individuals. Our report emphasizes that the Varicella zoster virus booster vaccine may be necessary to prevent not only acute varicella, but also its postinfectious neurologic complications.

A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the proteolipid protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.

Purpose To describe the visual outcomes of a large cohort of pediatric patients presenting to a tertiary care pediatric hospital with first-episode optic neuritis. Design Retrospective, observational cohort study. Methods In a tertiary care pediatric hospital, patients with first-episode optic neuritis and at least 3 months of follow-up over a 10-year period were assessed and followed-up in the ophthalmology department. The main outcome measures were visual acuity at 3 months and 1 year of follow-up, with analysis of risk factors for poor visual outcomes and the time course of visual recovery. Results Of the 59 pediatric patients with first-episode optic neuritis, 46 had at least 3 months of follow-up and 36 had at least 1 year of follow-up. The mean age was 12.6 years old; 72% were female, 41% had bilateral involvement, 52% had or developed an underlying diagnosis (39% multiple sclerosis, 7% acute disseminated encephalomyelitis, 7% neuromyelitis optica), and 91% received treatment (85% steroids, 7% multimodal). At 1 year, 81% were at least 20/20 and 89% were at least 20/40. A poor visual outcome at 1 year ( P = 0.041). Other clinical characteristics, including visual acuity at presentation, sex, bilateral involvement, optic nerve edema, and underlying diagnoses were not significantly associated with poor visual outcomes. Conclusions In this cohort of pediatric patients with optic neuritis, the majority of patients regained normal visual acuity at 1 year, regardless of baseline clinical characteristics.

Epilepsy is a debilitating condition, often with neither a known etiology nor an effective treatment. Autoimmune mechanisms have been increasingly identified.To conduct a population-level study investigating the relationship between epilepsy and several common autoimmune diseases.A retrospective population-based study using claims from a nationwide employer-provided health insurance plan in the United States. Participants were beneficiaries enrolled between 1999 and 2006 (N = 2 518 034).We examined the relationship between epilepsy and 12 autoimmune diseases: type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves disease, Hashimoto thyroiditis, Crohn disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease.The risk of epilepsy was significantly heightened among patients with autoimmune diseases (odds ratio, 3.8; 95% CI, 3.6-4.0; P .001) and was especially pronounced in children (5.2; 4.1-6.5; P .001). Elevated risk was consistently observed across all 12 autoimmune diseases.Epilepsy and autoimmune disease frequently co-occur; patients with either condition should undergo surveillance for the other. The potential role of autoimmunity must be given due consideration in epilepsy so that we are not overlooking a treatable cause.

Background: Pediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS. Methods: A common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression. Results: The mean number of T2 lesions was 24.30 ± 19.68 (range:1–113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0–32). Individual lesion size ranged from 14.31 to 55750.60 mm 3 . Non-white subjects had higher T2–LV (unadjusted pT2-LV= 0.028; adjusted pT2-LV= 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07). Conclusion: Assessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS. Background Multiple sclerosis (MS) is an increasingly recognized disorder in children and adolescents. The onset of MS prior to the age of 18 occurs in 3-5% of the total MS population [1-3]. Children and adolescents with MS have higher relapse rates than adults with the disease [4], suggesting inflammation as a prominent feature. Children also demonstrate considerable cognitive disability early in the disease course [5-7] but relatively less

Antibodies against the myelin glycolipid galactosylceramide are widely used to study the distribution and function of this molecule. However, anti-galactosylceramide antibodies are not monospecific and have been shown to recognize epitopes carried not only by other glycolipids, but also by proteins. Using expression cloning we have identified a human kidney cDNA which induces a cell-surface protein recognized by the anti-galactosylceramide monoclonal antibody R-mab. These findings further support the idea that cross-reactive proteins may mediate some of the biological effects of the anti galactosylceramide antibodies.

Background Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs. Objective To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States. Design, setting, and patients A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States. Intervention We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS. Main outcome measure Disease stability as represented by lack of medication change for breakthrough disease. Results Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children. Conclusion Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.

Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis., Graphical abstract, Highlights • Pain is a major presenting symptom in children with myelitis. • Currently used imaging has limited sensitivity to myelin content. • We provide a summary on pediatric demyelinating conditions. • We review pain involvement and pathways affected by demyelination. • We review imaging modalities for the diagnosis and monitoring of myelitis.

Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD) and discuss the literature on this topic.