Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

Correlation between early computed tomography findings and neurological outcome in pediatric traumatic brain injury patients.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children. Head computed tomography (CT) is frequently utilized for evaluating trauma-related characteristics, selecting treatment options, and monitoring complications in the early stages. This study assessed the relationship between cranial CT findings and early and late neurological outcomes in pediatric TBI patients admitted to the pediatric intensive care unit (PICU). The study included children aged 1 month to 18 years who were admitted to the PICU due to TBI between 2014 and 2020. Sociodemographic data, clinical characteristics, and cranial CT findings were analyzed. Patients were categorized based on their Glasgow Coma Scale (GCS) score. Of the 129 patients, 83 (64%) were male, and 46 (36%) were female, with a mean age of 6.8 years. Falls (n = 51, 39.5%) and in-vehicle traffic accidents (n = 35, 27.1%) were the most common trauma types observed. Normal brain imaging findings were found in 62.7% of the patients, while 37.3% exhibited intracranial pathology. Hemorrhage was the most frequent CT finding. Severe TBI (n = 26, p = 0.032) and mortality (n = 9, p = 0.017) were more prevalent in traffic accidents. The overall mortality rate in the study population was 10.1%. In children with TBI, cranial CT imaging serves as an essential initial method for patients with neurological manifestations. Particularly, a GCS score of ≤ 8, multiple hemorrhages, diffuse cerebral edema, and intraventricular bleeding are associated with sequelae and mortality.

Management of Status Epilepticus by Different Pediatric Departments: Neurology, Intensive Care, and Emergency Medicine.

INTRODUCTION: The aim of this study was to explore the differences in status epilepticus (SE) management among pediatric neurology, emergency medicine, and intensive care specialists in Turkey. METHODS: A 22-item questionnaire regarding first-, second-, and third-line management strategies of SE including demographic characteristics and common etiologies according to the specialty of participants was mailed to 370 specialists working in Turkey. RESULTS: A total of 334 participants (response rate 90%) comprising 136 pediatric neurologists, 102 pediatric emergency medicine specialists, and 96 pediatric intensive care specialists completed the survey. While intensive care specialists frequently managed SE due to metabolic and autoimmune reasons, the most common etiologies encountered by emergency medicine specialists were epilepsy and infections. More than half of the intensive care specialists (64.6%) reported using non-BZD antiseizure medications in the 5th minute of the seizure. Most of the neurologists (76.4%) preferred to administer intravenous (IV) levetiracetam infusion as a second-line agent. About half of intensive care specialists and neurologists tried immunomodulatory therapies in super-refractory SE. Intensive care and emergency medicine specialists were less likely to favor ketogenic diet and pyridoxine therapy for the treatment of super-refractory SE. The rate of requesting EEG monitoring to recognize nonconvulsive SE (NCSE) was found to be very low except for neurologists. CONCLUSION: There was no consensus among neurologists, intensive care specialists, and emergency medicine specialists in the management of SE in Turkey. Familiarity with particular antiseizure medications and the etiologies they manage seem to be the most important factors influencing the attitudes.

Risk of seizure relapse and long-term outcomes after discontinuation of antiseizure medication in children with epilepsy.

OBJECTIVES: The aims of this study were to evaluate the demographic and clinical characteristics of children with epilepsy who discontinued their antiseizure medication (ASM), to determine potential predictors of seizure relapse, to calculate the rate of seizure relapse, and to detect long-term seizure outcomes. METHODS: A total of 269 seizure-free children with epilepsy who were decided to discontinue their ASM and were followed up for at least 18 months after ASM withdrawal were retrospectively evaluated. RESULTS: The enrolled children had been followed up for a median of 46 months (range 18-126 months; IQR: 29-61) after ASM withdrawal and 90 (33.5%) of their seizures relapsed. The median time to seizure relapse was 8 months (range 0.23-117 months; IQR: 2-25). Seizure relapse occurred in 16.7% of the 90 children at 1 month, 45.6% at 6 months, 62.2% at 1 year, 74.4% at 2 years, and 94.4% at 5 years. Univariate logistic regression analyses revealed six predictors significantly related to relapse: age at first seizure, age at diagnosis of epilepsy, intellectual disability, EEG findings after ASM withdrawal, ASM tapering time, and number of seizures on ASM. In multivariate logistic regression analyses, age at first seizure, intellectual disability, and ASM tapering time were not significantly associated anymore. The other three remained independently predictive. Pharmacological control of seizures with monotherapy was restored in 93.3% of the children with seizure relapse. CONCLUSION: This study evaluated potential predictors of seizure relapse, some of which have rarely been evaluated in previous studies. Adolescent age at diagnosis, abnormal EEG findings after ASM withdrawal, and high number of seizures on ASM were associated with a higher risk of seizure relapse. Abnormal MRI findings such as malformations of cortical development and hydrocephalus may be potential biomarkers for the risk of seizure relapse.

Comparison of Sublingual and Intramuscular Administration of Vitamin B12 for the Treatment of Vitamin B12 Deficiency in Children.

BACKGROUND: In most countries, contrary to some disadvantages, such as pain, relatively higher cost, and poor adherence to treatment, intramuscular (IM) route is still the primary treatment method for Vitamin B12 (VB12) deficiency. In recent years, because of these difficulties, new treatment methods are being sought for VB12 deficiency. OBJECTIVES: We aimed to compare sublingual (SL) and IM routes of VB12 administration in children with VB12 deficiency and to compare the efficacy of methylcobalamin and cyanocobalamin therapy in these children. METHODS: This retrospective study comprised 129 patients with VB12 deficiency (serum Vitamin 12 level ≤ 200 pg/mL) aged 5-18 years. Based on the formulations of Vitamin 12, we divided the patients into three treatment groups as IM cyanocobalamin, SL cyanocobalamin, and SL methylcobalamin. RESULTS: After Vitamin 12 therapy, serum Vitamin 12 levels increased significantly in all patients, and there was a statistically significant difference between the treatment groups (p < 0.05). CONCLUSIONS: SL cyanocobalamin and methylcobalamin were found as effective as IM cyanocobalamin for children with Vitamin 12 deficiency in correcting serum Vitamin 12 level and hematologic abnormalities.

Paroxysmal Tonic Upgaze in Children: Three Case Reports and a Review of the Literature.

BACKGROUND: In clinical practice, nonepileptic paroxysmal events during infancy and childhood are common reasons for parents and caregivers to seek for medical advice. These events are mostly unrecognized and considered as an epileptic seizure because of the clinical features resembling an epileptic seizure. Paroxysmal tonic upgaze, which consists of recurrent episodes of sustained upward deviation of the eyes and incomplete downward saccades, and normal horizontal eye movements without impairment of consciousness, is a diagnostic challenge for the pediatrician and pediatric neurologist. In general, the entity was defined as an apparently benign phenomenon with normal investigations and eventual complete resolution of the symptoms, although some authors reported on patients with associated neurologic signs, such as ataxia, developmental delay, and abnormal brain magnetic resonance imaging finding. METHODS: The patients were 3 children (1 boy and 2 girls) who were between 5 and 18 months old experiencing rapid ocular movements with sustained conjugate upward deviation of the eyes. Their attacks, which were recorded using a video or electroencephalogram system, were also investigated comprehensively, including neurologic examination, electroencephalograms, brain magnetic resonance imaging, and metabolic tests. Paroxysmal tonic upgaze attacks have decreased in number or disappeared in 2 patients, but 1 patient exhibited mild abnormalities on magnetic resonance imaging and had relatives with epilepsy. CONCLUSIONS: In conclusion, paroxysmal tonic upgaze is an apparently benign phenomenon with unclear pathophysiology of various proposed mechanisms such as genetic predisposition, immaturity of the brain stem, neurotransmitter depletion, or immune dysregulation. It is important to recognize the clinical presentation of paroxysmal tonic upgaze and distinguish the disorders from epilepsy for deciding the treatment and prognosis of the patients.

High rates of malnutrition and epilepsy: two common comorbidities in children with cerebral palsy

Background/aim: The aim of this study was to evaluate the nutritional status of children with cerebral palsy and determine the particular characteristics of the disorder. Materials and methods: The nutritional status of the children was assessed by the Gomez classification using weight-for-age. The Gross Motor Function Classification System was used to determine the gross and fine motor functions. Results: The study was conducted with 197 children (58.4% males) between the ages of 1 and 18 years old. Asphyxia (44.1%) was the primary etiological factor, and spastic quadriplegia (41.6%) was the most common type of cerebral palsy. Malnutrition was the most frequent comorbidity and the overall malnutrition rate was 76.6%. The most common type of malnutrition was severe malnutrition, which was seen in 70 patients (35.5%). Epilepsy was the second most common comorbidity, seen in 51.7% of the cases. Conclusions: Our results revealed a high rate of malnutrition and epilepsy in children with cerebral palsy. These two more common significant comorbidities that influence the outcomes of children with cerebral palsy should be carefully evaluated and successfully managed. Families of children with cerebral palsy and their physicians should be educated about the nutritional status in these children.

A Turkish case of galactosialidosis with a new homozygous mutation in CTSA gene.

Galactosialidosis is an autosamal reressive lysosomal storage disease caused by a combined deficiency of lysosomal ß-galactosidase and neuraminidase, due to a primary defect in protective protein/cathepsin A. Three subtypes are recognized: the early infantile type, the late infantile type, and the juvenile/adult type. We report here a female patient with early infantile galactosialidosis who was born at 35 weeks of gestation. After birth she remained at the neonatal intensive care unit. Physical examination revealed, coarse facial features, hepatomegaly, cardiac murmur and diffuse hypotonia. The patient's mother had a past history of fetal hydrops history. The diagnosis of galactosialidosis was confirmed by decreased activity of ß-galactosidase and undetectable neuraminidase activity in fibroblasts. Genetic examination revealed a new homozygous mutation (c.1284delG) in the CTSA gene.

Knowledge of, perceptions of, attitudes and practices regarding epilepsy among medical students in Turkey.

PURPOSE: Medical practitioners' attitudes have a significant impact on the quality of care for patients with epilepsy. This study was conducted to assess the current level of knowledge about epilepsy and treatment together with attitudes and perception toward patients with epilepsy among medical students in Turkey. METHOD: The study was conducted using a structured questionnaire to assess knowledge, awareness, and practices about epilepsy among medical students at Selçuk University, Konya, Turkey. RESULTS: Eight hundred and ninety subjects were interviewed, and 73.5% reported their awareness about epilepsy. Of these, 38.1% knew someone who had epilepsy, and 38.5% had witnessed an epileptic seizure. Although most of the students had heard about epilepsy, 38.4% of the students believed that epilepsy was primarily a genetic disease. About one-fifth of the students attributed the causes of epilepsy to vitamin deficiency (8.8%) and psychiatric (19.1%), infectious (19.5%), mental (4.4%), and hematological disorders (3.4%). According to 4.8% of the students, epilepsy could be a punishment from God, and 2.1% of students thought that it could be caused by an evil spirit. Eighty-eight percent considered epilepsy as a dangerous disease, and most of them thought that epilepsy is a lifelong condition. Fifty point six percent indicated that putting an object into the patient's mouth to prevent tongue-biting during a seizure is appropriate while 91.9% stated that drug therapy was the only treatment available for epilepsy. The most common negative attitudes toward people with epilepsy were students' objection to marrying someone with epilepsy and patients with epilepsy having children. CONCLUSION: Misconceptions about the causes, treatment, and nature of epilepsy are common among medical students at a Turkish medical school. Negative attitudes toward patients with epilepsy still exist. Medical school training programs should be designed to increase awareness of students about epilepsy.

Public awareness, knowledge, and practice relating to epilepsy among adults in Konya.

INTRODUCTION: This study aimed to determine the familiarity with, knowledge of, misunderstandings, and attitudes toward epilepsy among a group of Turkish adults living in Konya, an urban city in central Turkey. METHODS: By using an established familiarity-knowledge-attitudes practice questionnaire, 500 randomly selected adult residents of Konya were interviewed face-to-face. Demographic and sociocultural factors that predicted negative attitudes were determined. RESULTS: More than half of all participants (68.4%) reported hearing or reading about epilepsy, 44% knew someone with epilepsy, and 42.2% had witnessed a seizure. The primary source of knowledge was via relatives and friends; Negative attitudes were about marriage and inability to live alone with epilepsy (63.2% objected to marriage and 84% objected to living alone). A preconception of epilepsy being a dangerous and lifelong disease was the primary reason for negative attitudes. Predictors of negative attitudes were female gender, lower educational status, and living in a rural area. CONCLUSION: Negative attitudes regarding the marital status of patients with epilepsy still exist. These may stem from misconceptions about the cause and treatability of epilepsy.

Abducens nerve palsy in a girl with incomplete Kawasaki disease.

Kawasaki disease (KD) is a systemic vasculitis that can involve the nervous system, including the cranial nerves. Central nervous system findings, especially irritability, lethargy, and aseptic meningitis, occur in 1-30 % of KD patients (1). Cranial nerve palsies are seen rarely, and abducens nerve palsy has been reported in only three children. We describe a 2.5-year-old girl with incomplete KD who developed transient abducens nerve palsy after intravenous immunoglobulin (IVIG) treatment.

Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3.

Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival.

Low Vitamin D Levels: Are Associated with Both Iron Deficiency and Anemia in Children and Adolescents?

We have read, with great interest, the recent article by Lee. In this excellent study, the authors investigated the association between vitamin D deficiency and anemia in a nationally representative sample of Korean children and adolescents. They concluded that vitamin D deficiency is associated with increased risk of anemia, especially iron deficiency anemia, in healthy female children and adolescents. We appreciate and congratulate the authors for having addressed such an important issue. However, we have some concerns regarding this report, which we would like to share with you. As a result, further studies are needed for the association between vitamin D deficiency and anemia. Factors affecting Vitamin D status and anemia such as measurement method, nutrition, medications, and infections should be considered to conclude an association between vitamin D and anemia. Therefore, we think that considering these confounders would add value to this well-written article.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with Sjögren`s syndrome in a child.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nervous system disease associated with polyautoimmunity. CASE: We report a previously healthy 13-year old boy who was referred to our outpatient clinic with gait disturbance and distal lower limb weakness that had been increasing for six months. The patient had decreased deep tendon reflexes in the upper extremities and absence in the lower extremities, reduced muscle strength in the distal and proximal lower extremities, muscle atrophy, drop foot, and normal pinprick sensations. The patient was diagnosed with CIDP as a result of clinical findings and electrophysiological studies. Autoimmune diseases and infectious agents were investigated in terms of triggering CIDP. Although there was no clinical sign other than polyneuropathy, he was also diagnosed with Sjögren`s syndrome due to positive antinuclear antibodies and antibodies against Ro52, and with autoimmune sialadenitis. After six months of monthly intravenous immunoglobulin and oral methylprednisolone treatments, the patient was able to dorsiflex his left foot and walk without support. CONCLUSIONS: To our knowledge, our case is the first pediatric case with the coexistence of Sjögren`s syndrome and CIDP. Therefore, we suggest investigating children with CIDP in terms of underlying autoimmune diseases such as Sjögren`s syndrome.

Brain Magnetic Resonance Imaging Findings of Pediatric Hemophagocytic Lymphohistiocytosis Could Be Diagnostic and Life-Saving.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal disease and may also present with central nervous system findings at the beginning without specific diagnostic criteria. Brain magnetic resonance imaging (MRI) findings are diverse and can also be diagnostic. We aimed to emphasize the importance of brain MRI findings in the early diagnosis of this fatal disease. METHODS: MRI findings, clinical presentations, treatment response, and prognosis of seven patients with HLH were described. RESULTS: There were seven pediatric patients who were initially diagnosed with HLH with neurological findings without systemic signs of HLH: four as primary, two as secondary, and one as possible primary HLH. All patients had contrast-enhancing diffuse cerebellar and brainstem lesions; patchy periventricular and callosal cerebral lesions were observed. Thalamus involvement was found in three (42.8%), corpus callosum involvement in six (85.7%), and cervical spinal involvement in one (14.2%). Patients were followed up with these MRI findings, with prediagnoses of toxic, metabolic, infectious, vascular, and demyelinating diseases. Not all patients met the HLH diagnostic criteria due to incomplete systemic/laboratory findings; therefore, only two were immediately directed for hematopoietic stem cell therapy. Four died shortly after admission, one patient could not be followed up after HLH treatment, and two patients who fulfilled the HLH diagnostic criteria underwent hematopoietic stem cell transplantation and survived. CONCLUSIONS: Brain MRI findings, especially in the presence of neurological findings, allow for early diagnosis, which can be life-saving. These common features in brain MRI findings should be evaluated with this suspicion and included in HLH diagnostic criteria.