Epstein-Barr virus noncoding RNA EBER1 promotes the expression of a ribosomal protein paralog to boost oxidative phosphorylation.

Epstein-Barr virus (EBV) is a highly successful pathogen that infects ~95% of the adult population and is associated with diverse cancers and autoimmune diseases. The most abundant viral factor in latently infected cells is not a protein but a noncoding RNA called EBV-encoded RNA 1 (EBER1). Even though EBER1 is highly abundant and was discovered over forty years ago, the function of EBER1 has remained elusive. EBER1 interacts with the ribosomal protein L22, which normally suppresses the expression of its paralog L22-like 1 (L22L1). Here we show that when L22 binds EBER1, it cannot suppress L22L1, resulting in L22L1 being expressed and incorporated into ribosomes. We further show that L22L1-containing ribosomes preferentially translate mRNAs involved in the oxidative phosphorylation pathway. Moreover, upregulation of L22L1 is indispensable for growth transformation and immortalization of resting B cells upon EBV infection. Taken together, our results suggest that the function of EBER1 is to modulate host gene expression at the translational level, thus bypassing the need for dysregulating host gene transcription.

Importance of Genetic Testing in Children With Generalized Epilepsy.

INTRODUCTION: Epilepsy is a neurological disorder characterized by the predisposition for recurrent unprovoked seizures. It can broadly be classified as focal, generalized, unclassified, and unknown in its onset. Focal epilepsy originates in and involves networks localized to one region of the brain. Generalized epilepsy engages broader, more diffuse networks. The etiology of epilepsy can be structural, genetic, infectious, metabolic, immune, or unknown. Many generalized epilepsies have presumed genetic etiologies. The aim of this study is to compare the role of genetic testing to brain MRI as diagnostic tools for identifying the underlying causes of idiopathic (genetic) generalized epilepsy (IGE). METHODS:  We evaluated the diagnostic yield of these two categories in children diagnosed with IGE. Data collection was completed using ICD10 codes filtered by TriNetX to select 982 individual electronic medical records (EMRs) of children in the Penn State Children's Hospital who received a diagnosis of IGE. The diagnosis was confirmed after reviewing the clinical history and electroencephalogram (EEG) data for each patient. RESULTS: From this dataset, neuroimaging and genetic testing results were gathered. A retrospective chart review was done on 982 children with epilepsy, of which 143 (14.5%) met the criteria for IGE. Only 18 patients underwent genetic testing. Abnormalities that could be a potential cause for epilepsy were seen in 72.2% (13/18) of patients with IGE and abnormal genetic testing, compared to 30% (37/123) for patients who had a brain MRI with genetic testing. CONCLUSION: This study suggests that genetic testing may be more useful than neuroimaging for identifying an etiological diagnosis of pediatric patients with IGE.

Use of Complementary and Alternative Medicine in Children with Neuromuscular Disorders Followed at Penn State Health Pediatric Muscular Dystrophy Association Care Center Clinic.

The exact prevalence of complementary and alternative medicine (CAM) use is not known in pediatric patients with neuromuscular diseases followed by any of the 150 Muscular Dystrophy Association (MDA) Care Center Clinics nationwide. This study describes the prevalence and variety of CAM usage in this population, while also assessing the prevalence of caregiver disclosure of CAM use and caregiver perception of provider support for CAM. Fifty-two caregivers of pediatric patients seen at Penn State Health's Pediatric MDA Care Center Clinic completed our online survey. Overall, 19.2% of caregivers reported CAM use by their child. Less than half of caregivers reported discussing CAM use with their child's neurologist (41.5%); however, a majority of respondents reported interest in using CAM for their child in the future (52.8%). Understanding the prevalence of CAM usage and disclosure in pediatric MDA clinics may facilitate safer use of CAM in this community.

Use of Integrative, Complementary, and Alternative Medicine in Children with Epilepsy: A Global Scoping Review.

(1) Background: Epilepsy is one of the most common chronic neurological disorders in childhood. Complementary and alternative medicine (CAM) use is highly prevalent in patients with epilepsy. Despite CAM's widespread and increasing popularity, its prevalence, forms, perceived benefits, and potential risks in pediatric epilepsy are rarely explored. (2) Methods: We performed a scoping review of the available literature on the use of CAM in pediatric epilepsy. (3) Results: Overall, global cross-sectional studies showed a variable degree of CAM usage among children with epilepsy, ranging from 13 to 44% in prevalence. Popular types of CAMs reported were supplements, cannabis products, aromatherapy, herbal remedies, dietary therapy, massage therapy, and prayer. Families often report that CAM is effective, although there are limited objective measures of this. Potential risks lie in the use of CAM, such as herbal remedies, and/or unregulated, contaminated, or unpurified products. Studies also underscored inadequate patient-physician discussions regarding CAM. (4) Conclusions: A better understanding of this topic would aid clinicians in guiding patients/families on the use of CAM. Further studies on the efficacy of the different types of CAM used, as well as potential side effects and drug interactions are needed.

Elsberg Syndrome with Mixed Presentation as Meningitis Retention Syndrome: A Pediatric Case Report and Comprehensive Review of the Literature.

Elsberg syndrome is a typically infectious syndrome that may cause acute or subacute bilateral lumbosacral radiculitis and sometimes lower spinal cord myelitis. Patients often present with various neurological symptoms involving the lower extremities, including numbness, weakness, and urinary disturbances such as retention. A 9-year-old girl with no significant past medical history presented with altered mental status, fever, urinary retention, and anuria and was found to have encephalomyelitis. An extensive diagnostic workup led to ruling out possible etiologies until identifying Elsberg syndrome. In this report, we describe a case of Elsberg syndrome caused by West Nile virus (WNV). To the best of our knowledge, this is the first reported case of its kind in the pediatric population. Utilizing PubMed and Web of Science databases, we reviewed the literature to describe the neurogenic control of the urinary system in correlation to a multitude of neurologic pathologies.

First Report of Tobacco Ringspot Virus Infecting Pawpaw Orchard (Asimina triloba (L.) Dunal) in North America.

Pawpaw (Asimina triloba (L.) Dunal, Annonaceae) is a fruit tree native to eastern North America, increasingly grown for commercial production in the United States (Callaway, 1992; Layne, 1996), Europe, and Western Asia (Brannan and Coyle, 2021; Lolletti et al., 2021). In 2012, virus-like symptoms were noticed in a 0.3 ha pawpaw orchard at Michigan State University Plant Pathology Research Station; ~30% of the trees presented symptoms which included foliar mosaic, vein yellowing, and necrosis, and were first mistaken for nutrient (magnesium/zinc) deficiency. Trees were treated for magnesium/zinc deficiency but continued to decline in fruit yield and overall vigor, and typically died within 3─4years after symptoms were first observed (Fig. S1). Preliminary testing using Agdia ImmunoStrips for cucumber mosaic virus, impatiens necrotic spot virus, tobacco mosaic virus, tomato spotted wilt virus and the genus Potyvirus were negative. However, icosahedral virus particles were observed by TEM (Fig. S2). To establish virus identity, we deep-sequenced tissue from a symptomatic pawpaw obtained from same site in summer 2021. Virus particles were purified , and virion-associated nucleic acids (VANA) were extracted using the Purelink viral RNA/DNA kit (Invitrogen) (Maclot et al., 2021). Both viral RNA and DNA were subjected to high-throughput sequencing (HTS) on the Illumina NextSeq 500 platform (GIGA, University of Liege, Belgium). A total of 574,274 trimmed reads (150 nt read length) were de novo assembled using Geneious Prime 2022.2.2 software (https://www.geneious.com) and subjected to BLASTn analysis. Two contigs of 7511 bp (average coverage: 1048) and 3924 bp (average coverage: 3012) showed 94% and 95% nt identities with tobacco ringspot virus (TRSV) RNA1 isolate YW (MT042825) and RNA2 isolate OH19 (MT561435) respectively. These two contigs (Accession no. OP589177 and OP589178) covered the complete TRSV genome for each segment. HTS found no other plant-associated viral / virus-like sequences in this symptomatic pawpaw sample. To further confirm TRSV infection, leaf extract from this sample was tested with RT-PCR using primers specific to the RdRp gene of TRSV RNA1 (Forward, 5'-TAACCTCATTGCAGTTGATCCTT-3'; Reverse, 5'-TAATTCAAGCTCAGGTCTCTTCT-3'; 739 bp amplicon) and the coat protein of TRSV RNA2 (Forward, 5'-TCATGCTTAAAGATGCAGATGTG-3'; Reverse, 5'-TATAAAGCTCCGCACTAGAAAACA-3'; 753 bp amplicon). Sanger sequence analysis showed 99.5% and 99.8% nt identity between the amplicons and the HTS contigs (RNA1 and RNA2 respectively) assembled from the pawpaw sample, and the amplicons likewise matched GenBank TRSV sequences (91.7% and 95.6% nt identities respectively with TRSV RNA1 isolate CmTX-H (MN504766) and TRSV RNA2 isolate IA-1-2017 (MT563079)). We further screened for TRSV infection in leaves from four symptomatic and three non-symptomatic pawpaw trees collected from the same site in 2022. RT-PCR revealed positive infection in all four symptomatic samples and one of the three (33%) non-symptomatic samples. Our results confirm the presence of TRSV infection in symptomatic pawpaw trees and emphasize the importance of also monitoring non-symptomatic trees. We confirmed graft transmission with 100% transmission rate observed in 200 trees grafted from a TRSV-infected pawpaw (Shenandoah cultivar), and investigation of other transmission vectors is on going. Because of TRSV's wide host range (Tolin, 2008), its broad transmission profile in other crops (via nematodes, thrips, seeds, sap inoculation, and grafting) (Hill and Whitham, 2014), and the notable decline observed in infected pawpaws from different cultivars (10-35, NC-1, Overleese, Pennsylvania-Golden, Shenandoah, Sunflower, Wabash), TRSV appears to pose a new threat to pawpaw orchards. To the best of our knowledge, this is the first report of TRSV infecting pawpaw in North America and the world.

A Case of Autosomal Recessive Intellectual Developmental Disorder Type 5 Presenting with Epilepsy.

Autosomal recessive intellectual developmental disorder type 5 (MRT5, OMIM # 611091) is caused by biallelic pathogenic variants, leading to loss of function of the NSUN2 gene which encodes a methyltransferase involved in several biological processes, ranging from stress response to neurodevelopment (Hussain 2021). The current literature shows that MRT5 typically manifests with intellectual disability, facial dysmorphism, juvenile cataracts, chronic nephritis, hearing impairment, seizures, cerebellar atrophy, and microcephaly (Pingree et al. 2021). We describe a case of a patient with MRT5 who developed epilepsy in his teens, a rare clinical presentation that has not yet been discussed at length in the literature. Our patient is a 15-year-old male with a history of autism, developmental delay, and focal epilepsy who underwent genetic testing and was found to have a homozygous frameshift mutation in NSUN2 predicted to cause loss of function. This case emphasizes that epilepsy can be a phenotypic manifestation in patients with MRT5.

SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy.

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child's clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70−90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.

Cefepime-Induced Nonconvulsive Status Epilepticus in a Pediatric Patient with Normal Renal Function.

Introduction: Cefepime, a fourth-generation cephalosporin, is known to risk the induction of neurotoxic impairment from confusion to nonconvulsive status epilepticus (NCSE). Neurotoxic effects of cefepime are most commonly evident in the setting of impaired renal function in adults; however, are rarely present in those with normal renal excretion function or in the pediatric population. Case: We present a case of a 16-year-old female with a complicated past medical history but no accounts of impaired renal function yet, after starting cefepime, presented with encephalopathy, intermittent stimulus-induced posturing, and was found to have NCSE. Discontinuation of cefepime and administration of additional antiepileptics provided significant improvement in EEG and allowed the patient to return to baseline within two days. Conclusion: Cefepime-induced nonconvulsive status epilepticus should be considered in any patient with or without impaired renal function that shows acute changes in mental status, and/or reduced consciousness, after initiating cefepime treatment.

Encephalitis with Extensive Cortical Brain Magnetic Resonance Imaging Changes Secondary to Myelin Oligodendrocyte Glycoprotein Antibody Disease.

BACKGROUND The relatively new autoimmune disorder, anti-myelin oligodendrocyte glycoprotein (MOG) disease is particularly interesting because of its broad range of presentations. This entity's appearance on magnetic resonance imaging (MRI) of the brain often makes identifying this disease a challenging process. Younger patients tend to present with an acute disseminated encephalomyelitis picture, with encephalopathy and multifocal neurological signs, while older patients are more likely to present with optic neuritis. We, however, report an atypical case of a patient who presented with encephalopathy, seizures, and significant cortical and subcortical gray matter involvement and was found to have anti-MOG positivity in serum. CASE REPORT A 17-month-old previously healthy boy presented to Emergency Department with fever, lethargy, vomiting, and left-sided weakness. Eventually, he required intubation due to a prolonged seizure. Continuous electroencephalogram captured several focal seizures, and MRI of the brain showed cortical and subcortical T2 hyperintensities. After extensive laboratory evaluation, he tested positive for anti-MOG antibody. He was empirically started on high-dose intravenous pulse methylprednisolone, followed by plasma exchange, given the poor response to the intravenous steroids. At the 5-month follow-up, the results of the neurological examination had dramatically improved, and MRI findings had largely resolved. CONCLUSIONS This case highlights the importance of suspecting anti-MOG antibody-mediated encephalitis, even while ruling out infectious etiologies, in children presenting with encephalopathy, seizures and MRI abnormalities. Prompt recognition would allow for less delay in treatment and hopefully improve prognosis.

Complementary and Alternative Medicine (CAM) use in Children with Epilepsy.

Complementary and alternative medicine (CAM) use by the pediatric population with epilepsy in rural Pennsylvania was studied to characterize the prevalence, perceived effectiveness, and reasons for CAM use. This study additionally assessed the adequacy of parent-physician communication regarding CAM usage. A telephone survey was administered to 200 parents/caregivers of children with epilepsy followed at Hershey Medical Center. Thirteen percent of respondents indicated CAM use by their child. Common types of CAM used were cannabis-related products such as CBD oil and medical marijuana. Forty-eight percent of CAM users chose to initiate CAM owing to dissatisfaction with the outcomes of antiseizure drugs. Fifty-nine percent noticed a decrease in seizure frequency with CAM use, and more than 11% of CAM users reported side effects from CAM. Eighty percent of CAM users had discussions regarding CAM with their child's neurologist. CAM use was found to be associated with increased seizure severity (P = .004) and the prior use of cannabidiol (Epidiolex) (P < .001) or the ketogenic diet (P = .001). Increased seizure severity and the prior use of Epidiolex or the ketogenic diet may be used as predictors for the identification of patients with a higher likelihood of using CAM. Interest in future CAM use, especially cannabis-related products, was expressed in a large percentage of non-CAM users. Given the high parental or caregiver interest in CAM, providers are encouraged to be proactive in initiating discussions about CAM and collaborate with parents/caregivers to ensure the safe usage of CAM among pediatric patients.

Acute Necrotizing Encephalopathy: 2 Case Reports on RANBP2 Mutation.

Infection-induced acute encephalopathy 3 (IIAE3) is an autosomal dominant disease resulting from a pathogenic variant in the RANBP2 gene. IIAE3 results in the susceptibility to the recurrence of acute necrotizing encephalopathy (ANE1) which presents as bilateral symmetric thalamic, midbrain and/or hindbrain lesions that typically develops within 1-4 days post-acute viral infection, commonly occurring before age 6.1-6 These case reports highlight a retrospective analysis of clinical data and radiographic studies on 2 ANE1 cases from our institution. The novel p.Leu450Phe variant of the RANBP2 gene was analyzed using in silico algorithms (PolyPhen-2, SIFT, Mutationtaster) which suggests the p.Leu450Phe variant is probably deleterious.7 An expansion of documented ANE1 case presentations and clinically significant RANBP2 gene mutations has the potential to improve long term outcomes if more informed therapeutic decision making can be achieved.