Complications of the Central Nervous System in Pediatric Patients With Common Cold Coronavirus Infection During 2014–2019

Background@#In pediatric patients, the common cold coronavirus (ccCoV) usually causes mild respiratory illness. There are reports of coronavirus causing central nervous system (CNS) infection in experimental animal models. Some immunocompromised patients have also been reported to have fatal CNS infections with ccCoV. The aim of this study was to investigate the clinical characteristics of CNS complications related to ccCoV infection. @*Methods@#From January 2014 to December 2019, a retrospective analysis was performed of medical records from hospitalized patients under 19 years of age whose ccCoV was detected through polymerase chain reaction in respiratory specimens. The CNS complications were defined as clinically diagnosed seizure, meningitis, encephalopathy, and encephalitis. @*Results@#A total of 436 samples from 420 patients were detected as ccCoV. Among the 420 patients, 269 patients were immunocompetent and 151 patients were immunocompromised.The most common type of ccCoV was OC43 (52% in immunocompetent, 37% in immunocompromised). CNS complications were observed in 9.4% (41/436). The most common type of CNS complication was the fever-provoked seizure under pre-existing neurologic disease (42% in immunocompetent and 60% in immunocompromised patients).Among patients with CNS complications, two immunocompetent patients required intensive care unit admission due to encephalitis. Three patients without underlying neurological disease started anti-seizure medications for the first time at this admission. There was no death related to ccCoV infection. @*Conclusion@#ccCoV infection may cause severe clinical manifestations such as CNS complications or neurologic sequelae, even in previously healthy children.

Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability

Intellectual disability (ID) is a neurodevelopmental disorder defined by below-average intelligence (intelligence quotient of <70) accompanied by adaptive behavior deficits. Defects in the functions of neural stem cells during brain development are closely linked to the pathogenesis of ID. To understand the molecular etiology of ID, we examined neural stem cells from individuals with Duchenne muscular dystrophy (DMD), a genetic disorder in which approximately one-third of the patients exhibit ID. In this study, we generated induced pluripotent stem cells from peripheral blood mononuclear cells from a normal individual and DMD patients with and without ID to identify ID-specific functional and molecular abnormalities. We found defects in neural ectoderm formation in the group of DMD patients with ID. Our transcriptome analysis of patient-derived neural stem cells revealed altered expression of genes related to the hippo signaling pathway and neuroactive ligand-receptor interaction, implicating these in the pathogenesis of ID in patients with DMD.

Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability

Intellectual disability (ID) is a neurodevelopmental disorder defined by below-average intelligence (intelligence quotient of <70) accompanied by adaptive behavior deficits. Defects in the functions of neural stem cells during brain development are closely linked to the pathogenesis of ID. To understand the molecular etiology of ID, we examined neural stem cells from individuals with Duchenne muscular dystrophy (DMD), a genetic disorder in which approximately one-third of the patients exhibit ID. In this study, we generated induced pluripotent stem cells from peripheral blood mononuclear cells from a normal individual and DMD patients with and without ID to identify ID-specific functional and molecular abnormalities. We found defects in neural ectoderm formation in the group of DMD patients with ID. Our transcriptome analysis of patient-derived neural stem cells revealed altered expression of genes related to the hippo signaling pathway and neuroactive ligand-receptor interaction, implicating these in the pathogenesis of ID in patients with DMD.

Antiepileptic Drugs in Children: Current Concept

An epileptic seizure is defined as the transient occurrence of signs and/or symptoms due to abnormally excessive or synchronous neuronal activity in the brain. The type of seizure is defined by the mode of onset and termination, clinical manifestation, and by the abnormal enhanced synchrony. If seizures recur, that state is defined as epilepsy. Antiepileptic drugs (AEDs) are the mainstay of treatment. Knowledge about initiating and maintaining adequate AEDs is beneficial for the clinician who treats children with epilepsy. This article will delineate the general principles for selecting, introducing, and discontinuing AEDs and outline guidelines for monitoring adverse effects. In general, AED therapy following a first unprovoked seizure in children is not recommended. However, treatment should be considered after a second seizure. In children and adolescents, if they are seizure-free for at least 2 years, attempts to withdraw medication/s should be made, taking into account the risks vs. benefits for the individual patient. The decision on when and what AED to use should be tailored according to the patient. For optimal treatment, the selection of adequate AEDs can be achieved by considering the precise definition of the patient's seizure and epilepsy syndrome. Continuous monitoring of both therapeutic and adverse effects is critical for successful treatment with AEDs.

A case of FLNA gene mutation with respiratory insufficiency and periventricular heterotopia

Filamin A is an actin-binding protein and, in humans, is encoded by FLNA gene in the long arm of X chromosome. Filamin A plays a role in the formation of cytoskeleton by crosslinking actin filaments in cytoplasm. FLNA mutations affect cytoskeletal regulatory processes and cellular migrating abnormalities that result in periventricular heterotopia. A 5-month-old girl was hospitalized because of breathing difficulty and was diagnosed as having periventricular heterotopia with laryngomalacia, cricopharyngeal incoordination, pulmonary hypertension, and chronic lung disease. A genetic test was performed to find the cause of periventricular heterotopia, and FLNA gene mutation (c.5998+1G>A) was confirmed for the first time in Korea. After discharge, she developed respiratory failure due to a viral infection at 8 months of her age. In spite of management with mechanical ventilation, she died of pneumothorax and pulmonary hemorrhage. Herein, we report a case of FLNA gene mutation who presented with periventricular nodular heterotopia with respiratory insufficiency.

Antiepileptic Drugs in Children: Current Concept

An epileptic seizure is defined as the transient occurrence of signs and/or symptoms due to abnormally excessive or synchronous neuronal activity in the brain. The type of seizure is defined by the mode of onset and termination, clinical manifestation, and by the abnormal enhanced synchrony. If seizures recur, that state is defined as epilepsy. Antiepileptic drugs (AEDs) are the mainstay of treatment. Knowledge about initiating and maintaining adequate AEDs is beneficial for the clinician who treats children with epilepsy. This article will delineate the general principles for selecting, introducing, and discontinuing AEDs and outline guidelines for monitoring adverse effects. In general, AED therapy following a first unprovoked seizure in children is not recommended. However, treatment should be considered after a second seizure. In children and adolescents, if they are seizure-free for at least 2 years, attempts to withdraw medication/s should be made, taking into account the risks vs. benefits for the individual patient. The decision on when and what AED to use should be tailored according to the patient. For optimal treatment, the selection of adequate AEDs can be achieved by considering the precise definition of the patient's seizure and epilepsy syndrome. Continuous monitoring of both therapeutic and adverse effects is critical for successful treatment with AEDs.

Management of Alcohol Withdrawal Syndrome and Alcohol Withdrawal Seizure

Alcohol withdrawal syndrome (AWS) is a common condition occurring after intentional or unintentional abrupt cessation of alcohol in an alcohol-dependent individual. AWS represents a major problem in our society and alcohol withdrawal seizure is the major cause of seizures encountered by neurology residents in the emergency department. Patients with AWS present with mild symptoms of tremulousness and agitation or more severe symptoms including withdrawal seizures and delirium tremens. Particularly, severe AWS can produce significant rates of the morbidity (complications) and mortality. When diagnosed and managed insufficiently, the morbidity and mortality rates increase. Nevertheless, patients with AWS may be neglected and are often marginalized and the teaching about AWS to neurology residents is usually minimal. Also, attending neurologists are often poorly informed on the topic. Although there is insufficient consensus about the optimal investigation and management, the purpose of this review is to serve as a summary of the appropriate identification and management of this important condition in a neurological setting.

Predictive and Prognostic Factors of Viral Encephalitis in Pediatric Patients

PURPOSE: Encephalitis is an inflammation affecting brain parenchyma. At the time of presentation, it may be difficult to differentiate between viral encephalitis and altered mental status or seizures during febrile illness. The aim of the present study is to identify the predictive factors and to determine the prognostic factors of viral encephalitis in children presenting as seizure with fever. METHODS: From the retrospective review of the medical records, children with seizures or altered mental status during febrile illness who presented to Samsung Medical Center between January 2008 and May 2013 were included in the study. RESULTS: 81 patients were enrolled in this study (female:male=32:49). The mean age at admission was 4.9±4.3 years (range 0–14 years old). The patients were categorized into two groups according to the clinical diagnosis: (1) Viral encephalitis (VIRAL ENC, n=66), (2) Complex febrile seizures imitating viral encephalitis(C-FS, n=15). The predictive factors of viral encephalitis were focal and/or lateralized abnormalities in electroencephalography (EEG) (P<0.001). CONCLUSION: EEG can be helpful to predict the viral encephalitis, in pediatric patient who shows delayed restoration of consciousness after seizure during febrile illness.

Value of Repeat Brain MRI in Children with Focal Epilepsy and Negative Findings on Initial MRI

OBJECTIVE: To evaluate the value of repeat brain magnetic resonance imaging (MRI) in identifying potential epileptogenic lesions in children with initial MRI-negative focal epilepsy. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent. During a 15-year period, 257 children (148 boys and 109 girls) with initial MRI-negative focal epilepsy were included. After re-evaluating both initial and repeat MRIs, positive results at repeat MRI were classified into potential epileptogenic lesions (malformation of cortical development and hippocampal sclerosis) and other abnormalities. Contributing factors for improved lesion conspicuity of the initially overlooked potential epileptogenic lesions were analyzed and classified into lesion factors and imaging factors. RESULTS: Repeat MRI was positive in 21% (55/257) and negative in 79% cases (202/257). Of the positive results, potential epileptogenic lesions comprised 49% (27/55) and other abnormalities comprised 11% of the cases (28/257). Potential epileptogenic lesions included focal cortical dysplasia (n = 11), hippocampal sclerosis (n = 10), polymicrogyria (n = 2), heterotopic gray matter (n = 2), microlissencephaly (n = 1), and cortical tumor (n = 1). Of these, seven patients underwent surgical resection. Contributing factors for new diagnoses were classified as imaging factors alone (n = 6), lesion factors alone (n = 2), both (n = 18), and neither (n = 1). CONCLUSION: Repeat MRI revealed positive results in 21% of the children with initial MRI-negative focal epilepsy, with 50% of the positive results considered as potential epileptogenic lesions. Enhanced MRI techniques or considering the chronological changes of lesions on MRI may improve the diagnostic yield for identification of potential epileptogenic lesions on repeat MRI.

Desensitization to Oxcarbazepine: Long-Term Efficacy and Tolerability

BACKGROUND AND PURPOSE: Antiepileptic drug (AED)-associated cutaneous adverse drug reactions can lead to the discontinuation of medications. The aim of this study was to determine the long-term efficacy and safety of performing desensitization to oxcarbazepine. METHODS: This study involved 20 patients who exhibited cutaneous adverse drug reactions associated with oxcarbazepine use between July 2009 and March 2016 at Samsung Medical Center. All of the participants had to discontinue oxcarbazepine despite presenting initially positive responses. Human leukocyte antigen genotyping was performed to detect the genetic predisposition to Stevens-Johnson syndrome. The desensitization to oxcarbazepine was performed with a starting dosage of 0.1 mg/day. Efficacy was evaluated by comparing the frequency of seizures before and at 1 and 3 years after desensitization. Adverse events occurring during desensitization and the retention rate after desensitization were also investigated. RESULTS: Nineteen patients (95%) safely completed the desensitization protocol. One withdrew owing to emotional problems that appeared to be associated with oxcarbazepine. The follow-up period was 4.6±1.2 years (mean±SD), and oxcarbazepine was maintained for more than 3 years after desensitization in 15 patients (83.3%). The response rates were 84.2% and 77.8% at 1 and 3 years after desensitization, respectively. Eight patients remained seizure-free for 3 years, and two discontinued all AEDs. Transient adverse reactions such as mild rash and itching were reported by five patients during desensitization. CONCLUSIONS: This study has demonstrated the long-term efficacy and safety of desensitization to oxcarbazepine in patients exhibiting cutaneous adverse drug reactions. This favorable outcome should encourage the implementation of desensitization in patients presenting with hypersensitivity to oxcarbazepine as an alternative strategy in clinical practice.

Malformations of cortical development: genetic mechanisms and diagnostic approach / 소아과

Malformations of cortical development are rare congenital anomalies of the cerebral cortex, wherein patients present with intractable epilepsy and various degrees of developmental delay. Cases show a spectrum of anomalous cortical formations with diverse anatomic and morphological abnormalities, a variety of genetic causes, and different clinical presentations. Brain magnetic resonance imaging has been of great help in determining the exact morphologies of cortical malformations. The hypothetical mechanisms of malformation include interruptions during the formation of cerebral cortex in the form of viral infection, genetic causes, and vascular events. Recent remarkable developments in genetic analysis methods have improved our understanding of these pathological mechanisms. The present review will discuss normal cortical development, the current proposed malformation classifications, and the diagnostic approach for malformations of cortical development.

Malformations of cortical development: genetic mechanisms and diagnostic approach / 소아과

Malformations of cortical development are rare congenital anomalies of the cerebral cortex, wherein patients present with intractable epilepsy and various degrees of developmental delay. Cases show a spectrum of anomalous cortical formations with diverse anatomic and morphological abnormalities, a variety of genetic causes, and different clinical presentations. Brain magnetic resonance imaging has been of great help in determining the exact morphologies of cortical malformations. The hypothetical mechanisms of malformation include interruptions during the formation of cerebral cortex in the form of viral infection, genetic causes, and vascular events. Recent remarkable developments in genetic analysis methods have improved our understanding of these pathological mechanisms. The present review will discuss normal cortical development, the current proposed malformation classifications, and the diagnostic approach for malformations of cortical development.

Using Array-Based Comparative Genomic Hybridization to Diagnose Pallister-Killian Syndrome

Pallister-Killian syndrome (PKS) is a rare multisystem disorder characterized by isochromosome 12p and tissue-limited mosaic tetrasomy 12p. In this study, we diagnosed three pediatric patients who were suspicious of having PKS using array-based comparative genomic hybridization (array CGH) and FISH analyses performed on peripheral lymphocytes. Patients 1 and 2 presented with craniofacial dysmorphic features, hypotonia, and a developmental delay. Array CGH revealed two to three copies of 12p in patient 1 and three copies in patient 2. FISH analysis showed trisomy or tetrasomy 12p. Patient 3, who had clinical features comparable to those of patients 1 and 2, was diagnosed by using FISH analysis alone. Here, we report three patients with mosaic tetrasomy 12p. There have been only reported cases diagnosed by chromosome analysis and FISH analysis on skin fibroblast or amniotic fluid. To our knowledge, patient 1 was the first case diagnosed by using array CGH performed on peripheral lymphocytes in Korea.

Clinical outcomes and neurodevelopmental outcome of prenatally diagnosed agenesis of corpus callosum in single center of Korea

OBJECTIVE: With recent advances and frequent use of prenatal ultrasound, the antenatal diagnosis of agenesis of the corpus callosum (ACC) is not rare in obstetrics practices. However, information regarding the long-term neurological outcome remains uncertain. The aim of this study was to investigate clinical outcomes of prenatally diagnosed ACC and to analyze postnatal neurodevelopmental outcomes of ACC neonates born in our single center. METHODS: We retrospectively reviewed 56 cases of prenatally suspected ACC referred to our center. RESULTS: Fifty-six fetuses were diagnosed with ACC, and 12 of those were followed-up in our center until delivery. Of the remaining 44, 7 were delivered after being referred back to the original hospital, 23 were lost to follow-up, and 14 had unknown outcomes. Among all 56, 29 were considered to have isolated ACC and 27 were considered to have non-isolated ACC. Of the 10 live fetuses delivered in our center, four had isolated ACC, three had non-isolated ACC, and the rest had outcomes unrelated to ACC. Neurodevelopmental outcome was followed-up until approximately age 3 years. Of the four with isolated ACC, three (75%) had normal neurodevelopmental outcomes. CONCLUSION: Similar to other studies, the results of our single-center study included positive neurodevelopmental outcomes for those with isolated ACC. However, despite our endeavor to counsel patients with prenatally diagnosed ACC, the delivery rate in our center was quite low. Therefore, larger, multicenter, retrospective studies including long-term neurological development outcomes are crucial and urgently needed to provide better counseling.

A Korean Patient with Early Juvenile Form of Metachromatic Leukodystrophy: Biochemical and Molecular Genetic Investigation

Metachromatic leukodystrophy is an inherited lysosomal storage disorder caused by the deficiency of arylsulfatase A activity. The patient in this study, a 5-yr-old girl, presented with progressive psychomotor regression. An MRI image of her brain showed bilateral symmetrical demyelination. The arylsulfatase A activity in her leukocytes was decreased to 8.0 nmol/hr/mg protein (reference range, 25-80 nmol/hr/mg protein). Mutation analysis of ARSA, using PCR and direct sequencing, showed two heterozygote pathogenic variations of c.449C>T (p.Pro150Leu) and c.640G>A (p.Ala214Thr). In summary, we report a Korean patient with an early juvenile form of metachromatic leukodystrophy, who was diagnosed based on her clinical symptoms as well as by using biochemical, radiological, and molecular genetic investigations.

Delayed Diagnosis of Atypical Mowat-Wilson Syndrome

No abstract available.

Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation

BACKGROUND AND PURPOSE: Given the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations. METHODS: Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation. RESULTS: Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups. CONCLUSIONS: This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients.

Clinical outcome of acute necrotizing encephalopathy in related to involving the brain stem of single institution in Korea / 소아과

PURPOSE: Acute necrotizing encephalopathy (ANE) is a fulminant disease of the brain characterized by bilateral thalamic lesions, and is prevalent among children in East Asia. The prognosis of ANE is usually poor with a high mortality rate and neurological sequelae. This study aimed to delineate the clinical characteristics and prognostic factors of ANE. METHODS: We retrospectively analyzed clinical data of 399 pediatric patients with encephalitis who were admitted to Samsung Medical Center from December 1998 to March 2011. We enrolled ten patients (11 cases) with ANE and analyzed their demographic, clinical, and neuroimaging data. The location and extent of the brain regions were checked based on fluid-attenuated inversion recovery, T1-, and T2-weighted imaging findings; the presence of contrast enhancement, restricted diffusion, and hemorrhage. RESULTS: Ten patients were identified, including one patient with two episodes. The median age of onset was 1.5 years (0.4-8.4 years). The mortality rate was 40%, and only 30% of patients survived without neurological sequelae. The definite involvement of the brainstem on brain magnetic resonance imaging was significantly correlated with mortality (P=0.04). CONCLUSION: Broad and extensive brainstem involvement suggested the fulminant course of ANE. Early diagnosis of ANE before brainstem involvement, through careful identification of symptoms of brain dysfunction, may be the best way to achieve better neurological outcomes.

Successful Treatment of Intractable Hiccups with Benztropine

In general, intractable hiccups are uncommon. Various drugs and interventions have been reported, but there is no consensus on the treatment of intractable hiccups. We report a patient with meningitis and rhombencephalitis who presented with intractable hiccups that were resolved following treatment with benztropine. A 17-year-old boy was admitted to another hospital with a two-week history of fever and headache. A cerebrospinal fluid (CSF) test showed an increased white blood cell (WBC) count (290/muL, monocytes 100%). He was diagnosed with meningitis and treated with ceftriaxone. Two days after admission, hiccups started and lasted for eight days, despite treatment with phenobarbital, diazepam, haloperidol, phenytoin, and chlorpromazine. He was transferred to our hospital for further evaluation and treatment. He was clinically diagnosed with rhombencephalitis based upon the findings of brain magnetic resonance imaging (MRI). The fever and headache disappeared one day later. However, the hiccups persisted, despite symptomatic treatment with chlorpromazine, gabapentin, and metoclopramide. The hiccups disappeared after one day of adding benztropine without relapse. Benztropine can be considered in the treatment of intractable hiccups.

Chordoid Meningioma in a Pediatric Patient with Tuberous Sclerosis Complex

No abstract available.