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OBJECTIVE: Epilepsy is a suitable target for gene panel sequencing because a considerable portion of epilepsy is now explained by genetic components, especially in syndromic cases. However, previous gene panel studies on epilepsy have mostly focused on pediatric patients. METHODS: We enrolled adult epilepsy patients meeting any of the following criteria: family history of epilepsy, seizure onset age ≤ 19 years, neuronal migration disorder, and seizure freedom not achieved by dual anti-seizure medications. We sequenced the exonic regions of 211 epilepsy genes in these patients. To confirm the pathogenicity of a novel MTOR truncating variant, we electroporated vectors with different MTOR variants into developing mouse brains. RESULTS: A total of 92 probands and 4 affected relatives were tested, and the proportion of intellectual disability (ID) and/or developmental disability (DD) was 21.7%. As a result, twelve probands (13.0%) had pathogenic or likely pathogenic variants in the following genes or regions: DEPDC5, 15q12-q13 duplication (n = 2), SLC6A1, SYNGAP1, EEF1A2, LGI1, MTOR, KCNQ2, MEF2C, and TSC1 (n = 1). We confirmed the functional impact of a novel truncating mutation in the MTOR gene (c.7570C > T, p.Gln2524Ter) that disrupted neuronal migration in a mouse model. The diagnostic yield was higher in patients with ID/DD or childhood-onset seizures. We also identified additional candidate variants in 20 patients that could be reassessed by further studies. SIGNIFICANCE: Our findings underscore the clinical utility of gene panel sequencing in adult epilepsy patients suspected of having genetic etiology, especially those with ID/DD or early-onset seizures. Gene panel sequencing could not only lead to genetic diagnosis in a substantial portion of adult epilepsy patients but also inform more precise therapeutic decisions based on their genetic background. PLAIN LANGUAGE SUMMARY: This study demonstrated the effectiveness of gene panel sequencing in adults with epilepsy, revealing pathogenic or likely pathogenic variants in 13.0% of patients. Higher diagnostic yields were observed in those with neurodevelopmental disorders or childhood-onset seizures. Additionally, we have shown that expanding genetic studies into adult patients would uncover new types of pathogenic variants for epilepsy, contributing to the advancement of precision medicine for individuals with epilepsy. In conclusion, our results highlight the practical value of employing gene panel sequencing in adult epilepsy patients, particularly when genetic etiology is clinically suspected.
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Epilepsia , Humanos , Adulto , Epilepsia/genética , Masculino , Femenino , Ratones , Animales , Serina-Treonina Quinasas TOR/genética , Adulto Joven , Adolescente , Persona de Mediana Edad , Mutación , Discapacidad Intelectual/genética , Pruebas GenéticasRESUMEN
BACKGROUND: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be more infectious and less severe than the other variants. Despite the increasing number of symptomatic patients, severe neurological complications in children with the Omicron variant have been reported rarely, unlike with wild-type or Delta variants. This study aimed to investigate severe neurological complications in children with Omicron variant infection. METHODS: We conducted a retrospective study of 17 pediatric patients with severe neurological manifestations associated with coronavirus disease 2019 in Korea during the Omicron variant prevalence, from January 1 to April 30, 2022. RESULTS: Among the 17 patients, 11 had pre-existing neurological disabilities and nine met the criteria for multisystem inflammatory syndrome in children (MIS-C). Four of the five vaccine-eligible patients (12 years and older) were unvaccinated. Severe neurological manifestations included acute necrotizing encephalopathy, acute fulminant cerebral edema, acute disseminated encephalomyelitis, basal ganglia encephalitis, unclassified severe encephalopathy/encephalitis, and refractory status dystonicus. Patients with MIS-C and underlying neurological disabilities had longer median hospital and intensive care unit stays compared with those without these conditions. Five patients survived with new neurological deficits at the one-year follow-up, and three died, all of whom had underlying neurological disabilities. CONCLUSIONS: This study shows that severe neurological complications in pediatric patients with the Omicron variant of SARS-CoV-2 occur infrequently but may lead to significant morbidity and mortality, especially among those with pre-existing neurological disabilities and unvaccinated individuals. Continued efforts are necessary to prevent and manage such complications in these vulnerable populations.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , Masculino , Femenino , Niño , Estudios Retrospectivos , Preescolar , Adolescente , República de Corea , Lactante , Enfermedades del Sistema Nervioso/etiología , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole-exome sequencing. All patients exhibited global developmental delay from early infancy, with motor development eventually reaching independent ambulation by 3 years of age. Language developmental delay varied significantly from nonverbal to simple sentences, which plateaued in all patients. Patients with the best language outcomes typically managed 2-3-word sentences, corresponding to a developmental age of 2-3 years. Epilepsy developed in 77% of patients, with onset consistently following developmental delays at a median age of 31 months. Longitudinal EEG data revealed a shift from occipital to frontal epileptiform discharges with age, suggesting a correlation with synaptic maturation. These findings suggest that the critical developmental plateau occurs between the ages of 2 and 5 years and is potentially influenced by epilepsy. By analyzing longitudinal data, our study contributes to a deeper understanding of SYNGAP1-related DEE, provides potential EEG biomarkers, and underlines the importance of early diagnosis and intervention to address this complex disorder.
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Electroencefalografía , Epilepsia , Genotipo , Mutación , Fenotipo , Proteínas Activadoras de ras GTPasa , Preescolar , Femenino , Humanos , Masculino , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Discapacidades del Desarrollo/fisiopatología , Epilepsia/genética , Epilepsia/patología , Epilepsia/fisiopatología , Secuenciación del Exoma , Estudios de Asociación Genética , Estudios Longitudinales , Mutación/genética , Proteínas Activadoras de ras GTPasa/genética , Estudios RetrospectivosRESUMEN
PURPOSE: To investigate the rate of development of symptomatic central nervous system (CNS) demyelinating attacks or recurrent optic neuritis (ON) after the first episode of ON and its risk factors for Korean pediatric patients. METHODS: This multicenter retrospective cohort study included the patients under 18 years of age (n=132) diagnosed with ON without previous or simultaneous CNS demyelinating diseases. We obtained the clinical data including the results of neuro-ophthalmological examinations, magnetic resonance images (MRIs), antibody assays, and laboratory tests. We investigated the chronological course of demyelinating disease with respect to the occurrence of neurological symptoms and/or signs, and calculated the 5-year cumulative probability of CNS demyelinating disease or ON recurrence. RESULTS: During the follow-up period (63.1±46.7 months), 18 patients had experienced other CNS demyelinating attacks, and the 5-year cumulative probability was 14.0±3.6%. Involvement of the extraorbital optic nerve or optic chiasm and asymptomatic lesions on the brain or spinal MRI at initial presentation were significant predictors for CNS demyelinating attack after the first ON. The 5-year cumulative probability of CNS demyelinating attack was 44.4 ± 24.8% in the AQP4-IgG group, 26.2±11.4% in the MOG-IgG group, and 8.7±5.9% in the double-negative group (P=0.416). Thirty-two patients had experienced a recurrence of ON, and the 5-year cumulative probability was 24.6±4.0%. In the AQP4-IgG group, the 5-year cumulative probability was 83.3±15.2%, which was significantly higher than in the other groups (P<0.001). CONCLUSIONS: A careful and multidisciplinary approach including brain/spinal imaging and antibody assay can help predict further demyelinating attacks in pediatric ON patients.
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Enfermedades Desmielinizantes , Neuromielitis Óptica , Neuritis Óptica , Humanos , Niño , Adolescente , Estudios Retrospectivos , Glicoproteína Mielina-Oligodendrócito , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/epidemiología , Encéfalo/metabolismo , Autoanticuerpos , Inmunoglobulina G , República de Corea/epidemiología , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/epidemiología , Acuaporina 4RESUMEN
Management of pediatric epilepsies poses unique challenges around diagnosis, treatment options, comorbidities, and the potential for these factors to interact with processes in the developing brain. In pediatric patients, broad-spectrum antiseizure medications (ASMs) with minimal potential for adverse events (AEs) and limited impact on cognition and behavior are preferred. Perampanel is a first-in-class ASM with broad-spectrum efficacy, a tolerable safety profile, minimal negative impact on cognitive function, and other features that make it a viable treatment option in this patient population. However, evidence and experience of its use in pediatric patients are less extensive than in adult patients. Experts in pediatric epilepsy across the region convened at a series of meetings to discuss the use of perampanel in pediatric patients, including dose optimization, AE prevention and management, and considerations in particular groups. This article summarizes key evidence for perampanel in the pediatric population and consolidates the experts' recommendations for using the ASM in managing pediatric epilepsies.
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Epilepsias Parciales , Epilepsia , Nitrilos , Piridonas , Adulto , Humanos , Niño , Epilepsias Parciales/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Testimonio de Experto , Resultado del Tratamiento , Epilepsia/tratamiento farmacológico , AsiaRESUMEN
OBJECTIVE: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain. METHODS: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome. RESULTS: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom. SIGNIFICANCE: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Humanos , Niño , Epilepsias Parciales/cirugía , Epilepsia Refractaria/cirugía , Sueño , Cognición , Resultado del Tratamiento , ElectroencefalografíaRESUMEN
ISCA2 loss of function leads to leukodystrophy and developmental regression (multiple mitochondrial dysfunctions syndrome 4 (MMDS4)). We present a first Korean case of MMDS4 presenting with rapid developmental regression and leukodystrophy after febrile episode, mimicking post-infectious encephalitis. The patient had displayed normal development until 12 months of age. At 13 months of age, one month after experiencing a post-vaccination fever, she quickly progressed to being unable to sit unassisted nor speak any words. Analysis of the cerebrospinal fluid (CSF) revealed lympho-dominant pleocytosis. Amino acid analysis of both the serum and CSF demonstrated elevated glycine exclusively in the CSF. Diffuse leukodystrophy was noted in the brain magnetic resonance image. Whole exome sequencing revealed compound heterozygous ISCA2 variants of c.166T>G, p.C56G and c.422A>C, p.Q141P. No evidence of mitochondrial disease other than bilateral optic atrophy was noted. In cases of early onset rapid developmental regression with leukodystrophy, MMDS4 should be considered.
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Objective: Although pediatric epilepsy is an independent disease entity, it is often observed in pediatric neurodevelopmental disorders (NDDs) as a major or minor clinical feature, which might provide diagnostic clues. This study aimed to identify the clinical and genetic characteristics of patients with epilepsy in an NDD cohort and demonstrate the importance of genetic testing. Methods: We retrospectively analyzed the detailed clinical differences of pediatric NDD patients with epilepsy according to their genetic etiology. Among 1,213 patients with NDDs, 477 were genetically diagnosed by exome sequencing, and 168 had epilepsy and causative variants in 129 genes. Causative genes were classified into two groups: (i) the "epilepsy-genes" group resulting in epilepsy as the main phenotype listed in OMIM, Epi25, and ClinGen (67 patients) and (ii) the "NDD-genes" group not included in the "epilepsy-genes" group (101 patients). Results: Patients in the "epilepsy-genes" group started having seizures, often characterized by epilepsy syndrome, at a younger age. However, overall clinical features, including treatment responses and all neurologic manifestations, showed no significant differences between the two groups. Gene ontology analysis revealed the close interactions of epilepsy genes associated with ion channels and neurotransmitters. Conclusion: We demonstrated a similar clinical presentation of different gene groups regarding biological/molecular processes in a large NDDs cohort with epilepsy. Phenotype-driven genetic analysis should cover a broad scope, and further studies are required to elucidate integrated pathomechanisms.
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BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating disorder of the central nervous system that is usually triggered by infections. We aimed to determine the temporal trends in the incidence of ADEM before and during the pandemic and their correlation with viral epidemiology. METHODS: We conducted a nationwide, population-based, retrospective, ADEM cohort study by using the Health Insurance Review and Assessment Service database. New-onset ADEM was defined as a patient (age <19 years) who was hospitalized with a diagnostic code of G04.0, G36.8, and G36.9 and a prescription of intravenous methylprednisolone. The National Infectious Disease Surveillance System was used to collect the nationwide viral epidemics. RESULTS: A total of 185 new-onset pediatric ADEM cases were included. The mean patient age was 7.0 ± 4.9 years. The incidence of ADEM was 0.34 to 0.48 of 100,000 persons per year before the pandemic, which dropped to 0.22 of 100,000 persons per year during the first pandemic year. The risk of ADEM occurrence was approximately 1.74% higher during the prepandemic years compared with the first pandemic year (odds ratio = 1.017, P = 0.009). There was a weak positive correlation between acute respiratory viral infection and ADEM incidence (r = 0.28, P = 0.03). CONCLUSION: This study demonstrates how infection control during the early coronavirus disease 2019 (COVID-19) pandemic influenced the incidence of ADEM. The low incidence of ADEM in the early COVID-19 pandemic may be related to the decline in acute respiratory viral infections, which are potential triggers of ADEM.
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COVID-19 , Encefalomielitis Aguda Diseminada , Niño , Humanos , Adulto Joven , Adulto , Preescolar , Encefalomielitis Aguda Diseminada/diagnóstico , Pandemias , COVID-19/epidemiología , COVID-19/complicaciones , Estudios de Cohortes , Estudios Retrospectivos , IncidenciaRESUMEN
The Korean Genetic Diagnosis Program for Rare Disease (KGDP) enrolled 1890 patients with rare diseases between March 2017 and October 2022. Children and adolescents accounted for the majority of the patients, and systemic disease was the most common presenting symptom. The exome-based virtual disease-specific multigene panel was the most frequently used analytical method, with an overall diagnostic yield of 33.3%. A total of 629 positive cases were diagnosed, involving 297 genes. All 297 genes identified in these cases were confirmed to be known genes listed in the OMIM database. The nationwide KGDP network and its cooperation with the Korean Undiagnosed Diseases Program (KUDP) provide a more comprehensive genetic analysis of undiagnosed cases. The partnership between the KGDP and KUDP has the potential to improve the diagnosis and treatment options for patients. In conclusion, KGDP serves as the primary access point or gateway to KUDP.
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Pueblo Asiatico , Enfermedades Raras , Adolescente , Niño , Humanos , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Bases de Datos Factuales , Exoma , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , República de CoreaRESUMEN
[This corrects the article DOI: 10.3389/fneur.2023.1125455.].
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α-Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies associated with the defective glycosylation of α-dystroglycan (α-DG). Eighteen genes associated with α-dystroglycanopathies have been identified, and the relative prevalence of genetic subtypes varies with ethnicity. Here, we investigated the clinical and genetic characteristics of α-DG-related muscular dystrophy in the Korean pediatric population. We analyzed the clinical characteristics and variant profiles of 42 patients with α-DG-related muscular dystrophies diagnosed by either reduced glycosylation of α-DG and/or genetic confirmation. Genotype-phenotype correlations were explored by a retrospective medical record review. The muscle-eye-brain disease/Fukuyama congenital muscular dystrophy was the most common phenotype (28/42, 66.7%). Homozygous or compound heterozygous variants were detected in 37 patients belonging to 34 unrelated families (37/42; 88.1%). Pathogenic variants were identified in FKTN (n = 24), POMGNT1 (n = 4), GMPPB (n = 4), FKRP (n = 2), POMT1 (n = 2), and ISPD (n = 1). Compound heterozygous retrotransposal insertions and deep-intronic variants in FKTN were the most common genotypes and were associated with severe phenotypes. This study suggests that α-DG-related muscular dystrophy has a wide range of genotypes and phenotypes according to ethnicity. A stratified genetic test according to ethnicity should be considered to diagnose α-DG-related muscular dystrophy.
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Distrofias Musculares , Síndrome de Walker-Warburg , Niño , Humanos , Distroglicanos/genética , Síndrome de Walker-Warburg/genética , Estudios Retrospectivos , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Distrofias Musculares/congénito , Genotipo , Fenotipo , Mutación , República de Corea/epidemiología , Pentosiltransferasa/genéticaRESUMEN
BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a rare type of autoimmune encephalitis. A characteristic faciobrachial dystonic seizure (FBDS) is also frequently associated with this disease. Although primarily reported in the adult population, reports of its occurrence in the pediatric population are rare. Here, we describe a case of a 6-year-old girl diagnosed with anti-LGI1 encephalitis that presented with cognitive decline and FBDS. CASE PRESENTATION: The girl was referred to a pediatric neurology department for uncontrolled seizures and dyskinesia. She initially presented with a memory deficit, abnormal movement of the limbs and trunk, and ataxia. Her cerebrospinal fluid exam was unremarkable, but her brain MRI showed focal T2 high signal intensity in the left anterior putamen and right caudate nucleus. In addition, there were refractory episodes of brief tonic or dystonic movement of the face and arms that were suggestive of FBDS. She was initially treated with intravenous methylprednisolone and phenobarbital, then given another pulse of methylprednisolone and intravenous immunoglobulin as her symptoms persisted. Tests for neuronal autoantibodies revealed the presence of anti-LGI1 antibodies. Subsequent human leukocyte antigen (HLA) typing resulted in the identification of HLA-DRB1 DR7(*07:01 g) DR9(*09:01 g). Screening for thymoma and other neoplasms showed no signs of a tumor. She was treated with rituximab, tocilizumab, and antiseizure medications, including oxcarbazepine, valproic acid, and lamotrigine. Her FBDS and cognitive symptoms showed substantial improvements. CONCLUSION: While it is known that anti-LGI1 encephalitis responds well to immunotherapy, our patient showed an incomplete response, requiring further therapy. This is the first report of a pediatric patient with anti-LGI1 encephalitis treated with tocilizumab.
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Discinesias , Encefalitis , Glioma , Encefalitis Límbica , Humanos , Adulto , Niño , Femenino , Leucina/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/uso terapéutico , Encefalitis/complicaciones , Encefalitis/tratamiento farmacológico , Autoanticuerpos , Convulsiones/tratamiento farmacológico , Metilprednisolona/uso terapéuticoRESUMEN
Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success rate and recurrence risk factors after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of a self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were negative factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure-free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.
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Epilepsia Generalizada , Epilepsia , Niño , Humanos , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Epilepsia Generalizada/tratamiento farmacológico , Factores de Riesgo , Factores de Tiempo , RecurrenciaRESUMEN
Objectives: Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy, often triggered by infection. We aimed to investigate how the incidence of GBS changed in the early stages of the coronavirus 2019 (COVID-19) pandemic when nationwide infections declined due to non-pharmaceutical interventions. Methods: We conducted a nationwide population-based retrospective GBS cohort study using data from the Health Insurance Review and Assessment Service of Korea. Patients with new-onset GBS were defined as those who were first hospitalized between 1 January 2016 and 31 December 2020 with an International Classification of Disease, 10th Revision code, for GBS (G61.0) as a primary diagnosis. The incidence of GBS in the pre-pandemic years (2016-2019) was compared with that in the first pandemic year (2020). Nationwide epidemiological data for infections were collected from the national infectious disease surveillance system. A correlation analysis was performed to determine the incidence of GBS and nationwide trends of various infections. Results: Overall, 3,637 new-onset GBS cases were identified. The age-standardized incidence of GBS in the first pandemic year was 1.10 (95% confidence interval, 1.01-1.19) per 100,000 persons. Compared to the first pandemic year, the incidence of GBS during the pre-pandemic years (1.33-1.68/100,000 persons/year) was significantly higher, with incidence rate ratios of 1.21-1.53 (P < 0.001). Nationwide cases of upper respiratory viral infections were significantly reduced in the first pandemic year; however, Campylobacter infections peaked in the summer of the pandemic. The nationwide epidemiology of parainfluenza virus, enterovirus, and Campylobacter infections correlated positively with GBS incidence. Conclusion: The overall GBS incidence decreased in the early stages of the COVID-19 pandemic, which can be attributed to the dramatic reduction in viral illnesses due to public measures.
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OBJECTIVE: Self-limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2-positive SeLIE only, and anti-seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2-positive SeLIE and to propose effective anti-seizure medications for seizure control. METHODS: We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal-onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2-related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti-seizure medications. RESULTS: Patients with PRRT2-related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short-duration (n = 33, 91.7%), and bilateral tonic-clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One-third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti-seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. SIGNIFICANCE: Our results delineated the clinical characteristics of PRRT2-positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti-seizure medications for initial clustered seizure control. If afebrile bilateral tonic-clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2-positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.
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Epilepsia Benigna Neonatal , Epilepsia , Lactante , Recién Nacido , Humanos , Epilepsia Benigna Neonatal/tratamiento farmacológico , Epilepsia Benigna Neonatal/genética , Epilepsia Benigna Neonatal/diagnóstico , Mutación , Estudios Retrospectivos , Bloqueadores de los Canales de Sodio , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Convulsiones/tratamiento farmacológico , Convulsiones/genéticaRESUMEN
BACKGROUND: Our study aimed to characterize seizure incidence and seizure outcome of pediatric autoimmune encephalitis (AE) focusing on subgroup analysis based on antibody (Ab). METHODS: Among 110 pediatric patients with AE, we compared seizure characteristics and outcomes in 68 patients with seizure, who satisfied the proposed criteria of pediatric AE. Accordingly, patients were classified into three groups, anti-myelin oligodendrocyte glycoprotein (anti-MOG) AE, anti-N-methyl-D-aspartic acid receptor (anti-NMDAR) AE, and Ab-negative AE. Univariate and multivariate analyses were performed to evaluate the risk factors for postencephalitic seizures, defined as persisting seizures six months after onset. RESULTS: Seizure incidence in the anti-NMDAR (88.9%) and Ab-negative (71.1%) groups differed from anti-MOG group (37.8%). Median seizure frequency within six months was higher in the Ab-negative group (6.0, interquartile range [IQR] 3.0 to 13.0) than in the anti-NMDAR group (3.0, IQR 2.0 to 4.5) and anti-MOG group (2.0, IQR 1.0 to 5.0). Patients in the Ab-negative group tended to develop postencephalitic seizures more frequently and have a lower seizure freedom rate than those in the anti-NMDAR and anti-MOG groups. Ab-negative status, high seizure frequency within six months, and the presence of status epilepticus were associated with the development of postencephalitic seizures on univariate analysis. On multivariate analysis, Ab-negative status remained the only significant variable linked with postencephalitic seizure (odds ratio, 4.17; 95% confidence interval, 1.02 to 18.05). CONCLUSIONS: We delineated the seizure incidence, evolution, and outcome of pediatric patients with Ab-positive and Ab-negative AE. Ab-negative status is predictive of higher seizure burden, more frequent development of postencephalitic seizures, and less favorable seizure outcome than anti-NMDAR and anti-MOG Ab-positive status.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Enfermedades Autoinmunes del Sistema Nervioso , Encefalitis , Enfermedad de Hashimoto , Humanos , Convulsiones/etiología , Convulsiones/complicaciones , Encefalitis/complicaciones , Encefalitis/epidemiología , Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/epidemiología , Glicoproteína Mielina-Oligodendrócito , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/epidemiología , AutoanticuerposRESUMEN
PURPOSE: Dysembryoplastic neuroepithelial tumors (DNETs) are slow-growing epilepsy-associated tumors. Low or normal 11C-methionine (MET) PET uptake helps to differentiate DNETs from other low-grade gliomas. However, diverse MET-PET uptake in DNETs has been observed. The aim of this study is to measure the clinical significance and prognostic value of MET-PET in DNET management. PATIENTS AND METHODS: Retrospective review of 26 DNET patients was done. Clinical characteristics, radiologic findings, and visual and quantitative MET-PET results were analyzed. PET uptake was calculated as the tumor-to-homotopic mirror ratio (TNRm) and tumor-to-contralateral cortex ratio (TNRc). The clinical activity of the tumors at the time of PET was classified into active and quiescent groups. The surgical outcome was defined as a composite of 2 different aspects: tumor progression and/or clinical events such as seizure recurrence or tumor bleeding. RESULTS: Twenty-seven MET-PET examinations (20 initial MET-PET and 7 MET-PET during follow-up) were included. Clinically active tumors at the time of PET presented significantly higher values of TNRm and TNRc than quiescent tumors. High MET-PET uptake by visual grading, TNRm ≥ 1.90, and TNRc ≥ 1.85 exhibited poor prognosis for event-free survival. CONCLUSIONS: MET-PET uptake correlates well with the clinical behavior of DNETs at the time of PET examination. Moreover, High MET-PET uptake is closely related to seizure recurrence if tumors are not entirely resected. Efforts to achieve gross total resection should be made for DNETs with high MET-PET uptake.
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Neoplasias Encefálicas , Glioma , Niño , Humanos , Radioisótopos de Carbono , Tomografía de Emisión de Positrones/métodos , Glioma/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Metionina , ConvulsionesRESUMEN
Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.