OBJECTIVE:This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). METHODS:Infants aged 2-24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high-dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal-to-hormonal, hormonal-to-nonstandard, vigabatrin-to-hormonal, and vigabatrin-to-nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3-month clinical remission using a binary logistic regression to estimate odds ratios (ORs). RESULTS:There were 153 infants with IESS who received second treatments. The highest rates of 3-month remission were among infants in the hormonal-to-vigabatrin (22/65, 34%) and vigabatrin-to-hormonal (9/26, 35%) groups, followed by vigabatrin-to-nonstandard (3/10, 30%), hormonal-to-hormonal (4/22, 18%), and hormonal-to-nonstandard (1/30, 3.3%). Compared to the hormonal-to-vigabatrin group (reference), fewer infants had remission in the hormonal-to-nonstandard group (OR = .07, 95% confidence interval [CI] = .01-.53), and there was a trend toward fewer infants in the hormonal-to-hormonal group (OR = .43, 95% CI = .13-1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. SIGNIFICANCE:This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Three large multi-center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of Down syndrome regression disorder (DSRD). Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset neuroimmunologic disorders. A single-center, retrospective chart review evaluating clinically documented infusion reactions was performed for individuals meeting international consensus criteria for DSRD and having IVIg infusions between 2019 and 2023. Infusion reactions were evaluated for severity and need for alterations in infusion plan. This cohort was compared against an age and sex matched cohort of children with neuroimmunologic conditions who had also received IVIg infusions. In total, 127 individuals with DSRD and 186 individuals with other neuroimmunologic disorders were enrolled. There was no difference in the overall rate of adverse reactions (AEs) between the DSRD and general neuroimmunology cohorts (p = 0.31, 95% CI: 0.80-2.00), but cardiac-related AEs specifically were more common among the DSRD group (p = 0.02, 95% CI: 1.23-17.54). When AEs did occur, there was no difference in frequency of pharmacologic intervention (p = 0.12, 95% CI: 0.34-1.13) or discontinuation of therapy (p = 0.74, 95% CI: 0.06-7.44). There was a higher incidence of lab abnormalities on IVIG among the general neuroimmunology cohort (p = 0.03, 95% CI: 0.24-0.94) compared to the DSRD cohort. Transaminitis was the most common laboratory abnormality in the DSRD group. In a large cohort of individuals with DSRD, there were no significant differences in the safety and tolerability of IVIg compared to a cohort of children and young adults with neuroimmunologic conditions.

Opsoclonus-myoclonus ataxia syndrome (OMAS) is a rare neuroimmunological disorder that affects one in 5 million children per year, 1 Pang K.K. de Sousa C. Lang B. Pike M.G. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol. 2010; 14: 156-161 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar typically presenting in the second year of life with chaotic eye movements (opsoclonus), muscle jerks (myoclonus), impaired motor coordination (ataxia), and irritability. 2 Hero B. Schleiermacher G. Update on pediatric opsoclonus myoclonus syndrome. Neuropediatrics. 2013; 44: 324-329 Crossref PubMed Scopus (42) Google Scholar Although previous studies suggest that outcomes tend to improve with early intensive immunosuppression, 3 Gorman M.P. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. 2010; 22: 745-750 Crossref PubMed Scopus (112) Google Scholar , 4 Dale R.C. Brilot F. Duffy L.V. et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014; 83: 142-150 Crossref PubMed Scopus (258) Google Scholar , 5 Mitchell W.G. Wooten A.A. O'Neil S.H. Rodriguez J.G. Cruz R.E. Wittern R. Effect of increased immunosuppression on developmental outcome of opsoclonus myoclonus syndrome (OMS). J Child Neurol. 2015; 30: 976-982 Crossref PubMed Scopus (63) Google Scholar a steering committee of pediatric neurologists and oncologists involved with the treatment of OMAS devised plans to organize an expanded research group from 2018 to 2020 and establish an international pediatric-onset opsoclonus-myoclonus ataxia syndrome (POOMAS) registry.

BackgroundPediatric onset multiple sclerosis (POMS) commonly occurs at the time of various endocrine changes. Evaluation of the impact of endocrine status on disease severity in POMS has not been previously explored.ObjectiveThis study sought to evaluate if sex and stress hormones in children with POMS impact motor and non-motor diseases severity.MethodsA single-center case control study was performed. Individuals with POMS were compared to individuals without neurologic disease. Each individual had three blood draws assessing stress and sex hormones between 07:00 and 09:00. Measures of fatigue (Epworth sleepiness scale), depression (PHQ-9), and quality of life (PedsQL) assessed at each visit.ResultsForty individuals with POMS and 40 controls were enrolled. Individuals with POMS had lower free testosterone (p = 0.003), cortisol (p < 0.001), and ACTH (p < 0.001) and had higher progesterone (p = 0.025) levels than controls. Relapses and EDSS were not impacted by endocrine variables. The POMS cohort had a significantly higher Epworth score (p < 0.001), PHQ-9 score (p < 0.001), and lower PQL score (p < 0.001) than controls. Non-motor measures were not associated with endocrine status.ConclusionFree testosterone, cortisol, ACTH, and progesterone were abnormal in children with POMS although there was no association between endocrine status and markers of disease severity or non-motor symptoms of MS.

Sexual and gender diversity (SGD)—an inclusive term describing people who identify outside of heteronormative binary concepts of gender and sexuality—directly affects us in the pediatric neurology clinic. SGD identity can impact various neurological conditions, including headache, epilepsy, and functional neurological disorders, all of which have been observed at higher rates in the SGD community.1-4 Gender-affirming hormone therapy can interact with medications commonly used to treat neurological conditions1,5,6 and may increase the risk for idiopathic intracranial hypertension7 and stroke.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Background and Objectives Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. Methods Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. Results The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. Discussion OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.

There is a gap in the literature regarding genetic underpinnings of pediatric autoimmune CNS diseases. This study explored rare gene variants implicated in immune dysregulation within these disorders. This was a single-center observational study of children with inflammatory CNS disorder who had genetic testing through next generation focused exome sequencing targeting 155 genes associated with innate or adaptive immunity. For in silico prediction of functional effects of single-nucleotide variants, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant were used, and Combined Annotation Dependent Depletion (CADD) scores were calculated. Identified genes were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Of 54 patients, 42 (77.8%) carried variant(s), among which 12 (22.2%) had 3–8 variants. Eighty-eight unique single-nucleotide variants of 55 genes were identified. The most variants were detected in UNC13D, LRBA, LYST, NOD2, DOCK8, RNASEH2A, STAT5B, and AIRE. The majority of variants (62, 70.4%) had CADD > 10. KEGG pathway analysis revealed seven genes associated with primary immunodeficiency (Benjamini 1.40E − 06), six genes with NOD-like receptor signaling (Benjamini 4.10E − 04), five genes with Inflammatory Bowel Disease (Benjamini 9.80E − 03), and five genes with NF-kappa B signaling pathway (Benjamini 1.90E − 02). We observed a high rate of identification of rare and low-frequency variants in immune regulatory genes in pediatric neuroinflammatory CNS disorders. We identified 88 unique single-nucleotide variants of 55 genes with pathway analysis revealing an enrichment of NOD2-receptor signaling, consistent with involvement of the pathway within other autoinflammatory conditions and warranting further investigation.

The two aims of this study were (i) to describe and expand the phenotypic spectrum of PIGT deficiency in affected individuals harboring the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant in either homozygous or compound heterozygous state, and (ii) to identify potential genotype-phenotype correlations and any differences in disease severity among individuals with and without the PIGT variants. The existing literature was searched to identify individuals with and without the two variants. A detailed phenotypic assessment was performed of 25 individuals (both novel and previously published) with the two PIGT variants. We compared severity of disease between individuals with and without these PIGT variants. Twenty-four individuals carried the PIGT variant Val528Met in either homozygous or compound heterozygous state, and one individual displayed the Asn527Ser variant in a compound heterozygous state. Disease severity in the individual with the Asn527Ser variant was compatible with that in the individuals harboring the Val528Met variant. While individuals without the Asn527Ser or Val528Met variant had focal epilepsy, profound developmental delay (DD), and risk of premature death, those with either of the two variants had moderate to severe DD and later onset of epilepsy with both focal and generalized seizures. Individuals homozygous for the Val528Met variant generally became seizure-free on monotherapy with antiepileptic drugs, compared to other PIGT individuals who were pharmaco-resistant. Two patients were diagnosed with myoclonic-atonic seizures, and a single patient was diagnosed with eyelid myoclonia. Our comprehensive analysis of this large cohort of previously published and novel individuals with PIGT variants broadens the phenotypical spectrum and shows that both Asn527Ser and Val528Met are associated with a milder phenotype and less severe outcome. Our data show that PIGT is a new candidate gene for myoclonic atonic epilepsy. Our genotype-phenotype correlation will be useful for future genetic counseling. Natural history studies of this mild spectrum of PIGT-related disorder may shed light on hitherto unknown aspects of this rare disorder.

OBJECTIVE:To compare the effectiveness of initial treatment for infantile spasms.METHODS:The National Infantile Spasms Consortium prospectively followed up children with new-onset infantile spasms that began at age 2 to 24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.RESULTS:Freedom from treatment failure rates were as follows: adrenocorticotropic hormone (ACTH) 88 of 190 (46%), oral steroids 42 of 95 (44%), vigabatrin 32 of 87 (37%), and nonstandard therapy 4 of 51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% confidence interval 34%-54%]). Changing from nonstandard therapy to ACTH would improve response from 8% to 39% (17%-67%), and changing to oral steroids would improve response from 8% to 38% (15%-68%). There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42% [15%-75%]), from vigabatrin to oral steroids (29% to 42% [28%-57%]), and from nonstandard therapy to vigabatrin (8% to 20% [6%-50%]). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p < 0.05).DISCUSSION:Compared to nonstandard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between that of ACTH/oral steroids and nonstandard therapy, although the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that for children with new-onset infantile spasms, ACTH or oral steroids were superior to nonstandard therapies.

The global pandemic of SARS-CoV-2 has been known to have diverse neurologic complications among adult patients. The neurologic effects of SARS-CoV-2 in the pediatric population is poorly described, especially in those with rare underlying neurologic conditions. We describe the first known case of SARS-CoV-2 in a pediatric patient with refractory opsoclonus-myoclonus syndrome. A 25-month-old female with progressive opsoclonus-myoclonus syndrome secondary to metastatic neuroblastoma status-post resection and chemotherapy presented with worsening opsoclonus, tremor, and breakthrough seizures. She had no fever or respiratory symptoms at presentation. Urine catecholamines were unchanged, with low suspicion for tumor recurrence. She was found to have SARS-CoV-2 via nasopharnygeal PCR assay. She received intravenous immunoglobulin and dexamethasone therapy with improvement in opsoclonus-myoclonus syndrome symptoms and was discharged home at her neurologic baseline. Patients with opsoclonus-myoclonus syndrome may present with exacerbation of symptoms in the context of SARS-CoV-2. This case describes a sentinel report of a child with opsoclonus-myoclonus syndrome presenting with worsening symptoms with concomitant SARS-CoV-2. Improvement in symptoms was achieved with standard of care therapies.

Background: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders. Methods: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKTI hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention. Results: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues. Conclusions: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management. (C) 2020 Elsevier Inc. All rights reserved.

Prevalence of Charcot-Marie-Tooth (CMT) Disease and chronic inflammatory demyelinating polyneuropathy (CIDP) are each reported between 1–20 per 100,000 individuals. Co-occurrence of these entities is not well delineated in current literature. We report 3 pediatric cases of genetically confirmed neuropathy and coexisting CIDP.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.