RESUMO
Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.
Assuntos
Epilepsias Parciais/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Canais de Potássio Ativados por Sódio , Morte Súbita do Lactente/genéticaRESUMO
AIM: To show that atypical multifocal Dravet syndrome is a recognizable, electroclinical syndrome associated with sodium channel gene (SCN1A) mutations that readily escapes diagnosis owing to later cognitive decline and tonic seizures. METHOD: Eight patients underwent electroclinical characterization. SCN1A was sequenced and copy number variations sought by multiplex ligation-dependent probe amplification. RESULTS: All patients were female (age range at assessment 5-26y) with median seizure onset at 6.5 months (range 4-19mo). The initial seizure was brief in seven and status epilepticus only occurred in one; three were febrile. Focal seizures occurred in four patients and bilateral convulsion in the other four. All patients developed multiple focal seizure types and bilateral convulsions, with seizure clusters in six. The most common focal seizure semiology (six out of eight) comprised unilateral clonic activity. Five also had focal or asymmetric tonic seizures. Rare or transient myoclonic seizures occurred in six individuals, often triggered by specific antiepileptic drugs. Developmental slowing occurred in all: six between 3 years and 8 years, and two around 1 year 6 months. Cognitive outcome varied from severe to mild intellectual disability. Multifocal epileptiform discharges were seen on electroencephalography. Seven out of eight patients had SCN1A mutations. INTERPRETATION: Atypical, multifocal Dravet syndrome with SCN1A mutations may not be recognized because of later cognitive decline and frequent tonic seizures.
Assuntos
Transtornos Cognitivos/etiologia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/diagnóstico , Deficiência Intelectual/etiologia , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Idade de Início , Criança , Desenvolvimento Infantil , Transtornos Cognitivos/genética , Variações do Número de Cópias de DNA , Eletroencefalografia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/genética , Dados de Sequência Molecular , Convulsões/genética , Convulsões/fisiopatologiaRESUMO
OBJECTIVE: To elucidate the presence and potential involvement of brain inflammation and cell death in neurological morbidity and intractable seizures in childhood epilepsy, we quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery. METHODS: Cortical tissue was collected from thirteen patients with intractable epilepsy due to focal cortical dysplasia (6), encephalomalacia (5), Rasmussen's encephalitis (1) or mesial temporal lobe epilepsy (1). Sections were processed for immunohistochemistry using markers for neuron, astrocyte, microglia or cellular injury. Cytokine assay was performed on frozen cortices. Controls were autopsy brains from eight patients without history of neurological diseases. RESULTS: Marked activation of microglia and astrocytes and diffuse cell death were observed in epileptogenic tissue. Numerous fibrillary astrocytes and their processes covered the entire cortex and converged on to blood vessels, neurons and microglia. An overwhelming number of neurons and astrocytes showed DNA fragmentation and its magnitude significantly correlated with seizure frequency. Majority of our patients with abundant cell death in the cortex have mental retardation. IL-1beta, IL-8, IL-12p70 and MIP-1beta were significantly increased in the epileptogenic cortex; IL-6 and MCP-1 were significantly higher in patients with family history of epilepsy. CONCLUSIONS: Our results suggest that active neuroinflammation and marked cellular injury occur in pediatric epilepsy and may play a common pathogenic role or consequences in childhood epilepsy of diverse etiologies. Our findings support the concept that immunomodulation targeting activated microglia and astrocytes may be a novel therapeutic strategy to reduce neurological morbidity and prevent intractable epilepsy.
Assuntos
Encéfalo/fisiopatologia , Encefalite/fisiopatologia , Epilepsia/fisiopatologia , Adolescente , Adulto , Astrócitos/fisiologia , Encéfalo/cirurgia , Morte Celular , Criança , Pré-Escolar , Doença Crônica , Citocinas/metabolismo , Epilepsia/cirurgia , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Microglia/fisiologia , Neuroimunomodulação/fisiologia , Neurônios/fisiologia , Convulsões/fisiopatologia , Convulsões/cirurgia , Adulto JovemRESUMO
To report the authors' experience with diagnosis and management of Dravet syndrome, or severe myoclonic epilepsy in infancy, in the era of commercially available genetic testing, the authors performed a retrospective study of 16 patients diagnosed with Dravet syndrome at a tertiary care pediatric epilepsy center. They analyzed their clinical presentation, electroencephalographic findings, genetic (SCN1A gene) results, and treatment responses and compared the findings to previous reports. The patients presented with all the previously described characteristics of Dravet syndrome. Six of the 7 patients (86%) who were tested for SCN1A mutations had positive results. The best treatment combinations included topiramate, valproate, or the ketogenic diet. Dravet syndrome is a well-defined epileptic syndrome that needs larger recognition, particularly because commercial testing for SCN1A gene mutations is now available in the United States. Despite its reputation for seizure intractability, several treatment options may be particularly helpful, whereas others need to be avoided.
Assuntos
Epilepsia Mioclônica Juvenil/genética , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Anticonvulsivantes/uso terapêutico , Análise Mutacional de DNA/métodos , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Epilepsia Mioclônica Juvenil/fisiopatologia , Epilepsia Mioclônica Juvenil/terapia , Canal de Sódio Disparado por Voltagem NAV1.1 , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
The notched delta pattern is one of the characteristic EEG features found in Angelman syndrome patients. The purpose of this study was to evaluate the possibility of using the notched delta pattern as a detection tool for Angelman syndrome patients by analyzing its frequency in a tertiary care pediatric center, its specificity for Angelman syndrome, and the age at which it was observed. The authors performed a retrospective review of the video-EEG recordings of all the patients who had either the notched delta pattern or a phenotype consistent with Angelman syndrome. The notched delta was observed in 1.1% of all the EEGs performed. Its specificity for Angelman syndrome was evaluated at 38%. The youngest age at which it was noted was 14 months. The results indicate that the notched delta pattern is relatively rare, but more frequent than expected, and is easily recognizable. The pattern was observed not only in Angelman syndrome patients, but also in children with a spectrum of conditions wider than reported. It is a powerful detection tool for Angelman syndrome when correlated to a suggestive phenotype, and the association of these features should raise suspicion for Angelman syndrome in both infants and adults.
Assuntos
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/fisiopatologia , Ritmo Delta , Fenótipo , Adolescente , Adulto , Síndrome de Angelman/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15 , Bases de Dados como Assunto/estatística & dados numéricos , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Gravação em Vídeo/métodosRESUMO
We present a case of a 9-month-old boy with a history of unequal hand movements, right-hand preference on physical examination, and cortical dysplasia on brain magnetic resonance imaging who was eventually diagnosed with cerebral palsy (CP). Although spasticity involving one or more limbs is the most common neurologic sign of CP, there can be a variety of other presenting symptoms including early hand preference, hypotonia, and oral motor dysfunction. In addition, traditional risk factors of premature birth and intrapartum complications are not always present. Given the wide clinical spectrum of CP, it is important for primary care providers to maintain a high index of suspicion to ensure appropriate diagnosis and early access to interventions.
Assuntos
Paralisia Cerebral/diagnóstico , Lateralidade Funcional , Paralisia Cerebral/fisiopatologia , Humanos , Lactente , Imageamento por Ressonância Magnética , MasculinoRESUMO
The purpose of this survey and record review was to characterize emergency department management of unprovoked seizures and status epilepticus in children in Illinois. The survey was sent to 119 participating emergency departments in the Emergency Medical Services for Children program; responses were received from 103 (88% response rate). Only 44% of the emergency departments had a documented protocol for seizure management. Only 12% of emergency departments had child neurology consultation available at all times. Record review showed that 58% of patients were discharged home, 26% were transferred to another institution, and 10% were admitted to a non-intensive care unit setting. Ninety percent of patients were treated with anticonvulsants. Seizure education was provided by the primary emergency department nurse (97%) and the treating physician (79%). This project demonstrated strengths and weaknesses in the current management of pediatric seizure patients in Illinois emergency departments.
Assuntos
Serviços Médicos de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Convulsões/terapia , Estado Epiléptico/terapia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Humanos , Illinois , Lactente , Educação de Pacientes como Assunto/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricosRESUMO
Workup of simple febrile seizures (SFS) has changed as the American Academy of Pediatrics made revisions to practice guidelines. In 2011, revisions were made regarding need for lumbar puncture (LP) as part of the SFS workup. This study surveyed more than 100 emergency departments regarding workup of children with SFS and performed a medical record review of workup that was performed. The survey shows that laboratory workup is done routinely and LP is done infrequently. The majority documents a complete exam. The medical record review demonstrates documentation of the examination, frequent laboratory and infrequent LP evaluation. Consistent with the American Academy of Pediatrics' revisions, survey and record reviews demonstrate that LP testing is infrequent. Contrary to the guideline, laboratory studies are routinely performed. This study suggests there is an opportunity to improve management of SFS by directing efforts toward finding the source of the fever and away from laboratory workup.
Assuntos
Serviço Hospitalar de Emergência/normas , Convulsões Febris/diagnóstico , Pré-Escolar , Registros Hospitalares , Humanos , Lactente , Internet , Guias de Prática Clínica como Assunto , Convulsões Febris/terapia , Punção Espinal/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
The pediatrician is often the first health professional notified of a child's first seizure. First seizures cause much anxiety for parents and practitioners. Parents are frightened as they witness a paroxysmal event that involves convulsions or altered mental status, and as a result, they seek answers, reassurance, and support. Every pediatrician faces the challenge of determining whether a child who had a paroxysmal event had a seizure. Therefore, it is important for the general pediatrician to have a good understanding of the diagnosis and management of a child's first seizure. This review will discuss the definition of seizures and epilepsy, the critical questions to answer during the initial evaluation of a child's first seizure, guidance for initial management, risk factors for seizure recurrence, and the value of electroencephalography in diagnosis and treatment.
Assuntos
Convulsões/diagnóstico , Criança , Diagnóstico Diferencial , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Epilepsia/etiologia , Epilepsia/terapia , Humanos , Pediatria , Recidiva , Fatores de Risco , Convulsões/epidemiologia , Convulsões/etiologia , Convulsões/terapia , Estados Unidos/epidemiologiaRESUMO
Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disability characterized by qualitative and persistent deficits in social communication and social interaction and by the presence of restricted, repetitive, and stereotyped patterns of behavior. Symptoms must be present in early childhood and they must limit and impair everyday functioning. There is an increased prevalence of epilepsy and/or epileptiform electroencephalography (EEG) abnormalities in children with ASD. It is estimated that approximately one-third of children and adolescents with ASD experience seizures, but the relationship between epilepsy and autism is controversial. This article reviews the types of seizures associated with ASD, the EEG findings, and current treatment strategies. The article also describes syndromes associated with the autism phenotype and epilepsy.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/complicações , Epilepsia/complicações , Criança , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/terapia , Terapia Combinada , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Epilepsia/terapia , Humanos , Imageamento por Ressonância Magnética , Fenótipo , Convulsões/complicações , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/terapiaRESUMO
Febrile seizures are the most common form of childhood seizures, affecting 2% to 5% of children. They are considered benign and self-limiting; however, a febrile seizure is a terrifying event for most parents, and is one of the most common causes of trips to the emergency room. A febrile seizure is "an event in infancy or childhood, usually occurring between 3 months and 5 years of age, associated with fever but without evidence of intracranial infection or defined cause." This definition excludes seizures with fever in children who have had a prior afebrile seizure. In 2011, The American Academy of Pediatrics (AAP) published a clinical practice guideline defining a febrile seizure as "a seizure accompanied by fever (temperature ≥ 100.4°F or 38°C by any method), without central nervous system infection, that occurs in infants and children 6 through 60 months of age." Febrile seizures are further classified as simple or complex. This article reviews the evaluation, management, and prognosis of simple and complex seizures, including febrile status epilepticus.