Encefalopatías epilépticas de inicio en recién nacidos y lactantes / Epileptic encephalopathies of onset in neonates and infants

Resumen Recientemente la Liga Internacional contra la Epilepsia (ILAE) socializó la clasificación propuesta para síndromes epilépticos de inicio neonatal y hasta los primeros 2 años de edad, dividiéndolos en síndromes epilépticos autolimitados y las encefalopatías epilépticas y del desarrollo (DEEs). En esta revisión nos dedicaremos a las DEEs, definidas como trastornos donde existe deterioro del desarrollo relacionado tanto con la etiología subyacente independiente de la actividad epileptiforme como con la encefalopatía epiléptica. Estas incluyen en el período neonatal la encefalopatía epiléptica infantil temprana o síndrome de Ohtahara y la encefalopatía mioclónica temprana, ahora agrupadas bajo la denominación de encefalopatías epilépticas y del desarrollo infantil temprano (EIDEE). El síndrome de espamos epilépticos infantiles, la epilepsia de la infancia con crisis migratorias y el síndrome de Dravet forman parte de las encefalopatías de inicio en el lactante. La importancia del reconocimiento temprano de las encefalopatías epilépticas radica no solo en el control de las crisis epilépticas, sino en detener el deterioro intentando cambiar el curso de la enfermedad. Es fundamental conocer la etiología evitando medicamentos que puedan exacerbar las crisis y empeorar el curso, aplicando medicina de precisión así como identificando pacientes candidatos a cirugía temprana de epilepsia.

Abstract The International League Against Epilepsy (ILAE) recently socialized the proposed classification for epileptic syndromes of neonatal onset and up to the first 2 years of age, dividing them into self-limited epileptic syndromes and epileptic and developmental encephalopathies (DEEs). In this review we will focus on DEEs, defined as disorders in which there is developmental impairment related to both the underlying aetiology independent of epileptiform activity and epileptic encephalopathy. These include early infantile epileptic encephalopathy or Ohtahara syndrome and early myoclonic encephalopathy in the neonatal period, now grouped under the name of epileptic and early childhood developmental encephalopathies (EIDEE). Infantile epileptic spasms syndrome, childhood epilepsy with migratory crises and Dravet syndrome are part of the infant-onset encephalopathies. The importance of early recognition of epileptic encephalopathies lies not only in the control of epileptic seizures, but also in stopping deterioration by trying to change the course of the disease. It is essential to know the etiology, avoiding medications that can exacerbate seizures and worsen the course, applying precision m edicine as well as identifying candidate patients for early epilepsy surgery.

Síndrome de Ohtahara: presentación de un caso asociado a Síndrome de Pierre Robin / Ohtahara syndrome: a case presentation associated with Pierre Robin syndrome

RESUMEN El Síndrome de Ohtahara es una encefalopatía epiléptica de inicio temprano en la vida, caracterizada por convulsiones intratables, trazado de ondassupresión, tanto en etapa de sueño como vigilia en electroencefalograma, y asociado a retraso en el desarrollo motor y cognitivo. Se presenta el caso de un niño, derivado a los quince días de vida al Hospital Nacional, Paraguay, para descartar cardiopatía congénita, debido a la dependencia de oxígeno. Al ingreso se constata aspecto facial coincidente con el síndrome de Pierre Robin, estridor laríngeo, hipotonía cervical y micropene. Internado se descarta cardiopatía congénita con ecocardiografía. Se asume dificultad respiratoria y necesidad de oxígeno secundarios a obstrucción respiratoria por glosoptosis. Ecografía transfontanelar revela hemorragia intraventricular grado II, imagen quística en fosa posterior, megacisterna versus quiste neuroepitelial. A los 47 días presenta convulsiones tónico-clónicas en miembros y posición de opistótonos, es medicado con AcidoValproico, luego Vigabatrina, sin respuesta. Trazado electroencefalográfico muestra patrón de descargas-supresión. Desarrolla infección asociada a cuidados de la salud con foco respiratorio, presenta mal manejo de secreciones y evolución tórpida, falleciendo a los 110 días. El caso se destaca por presentarse síndrome epiléptico en un paciente con fenotipo correspondiente al síndrome de Pierre Robin; pero que además tiene micropene. La presencia de las tres características citadas no pudo ser englobada dentro de un síndrome descripto con anterioridad. En recién nacidos con dismorfia y síndrome convulsivo es importante descartar la presencia de alteración estructural en el sistema nervioso como responsable del síndrome.

ABSTRACT Ohtahara syndrome is an epileptic encephalopathy that starts early in life, characterized by intractable seizures, wave-suppression tracing, both in the sleep and a waking phases of the electroencephalogram, and associated with delayed motor and cognitive development. We present the case of a child, to the fifteen days of life referred to the Hospital Nacional, Paraguay, with is the days of like to rule out congenital heart disease, due to oxygen dependence. On admission, the facial appearance was coincident with Pierre Robin syndrome, laryngeal stridor, cervical hypotonia and micropenis was observed. Once admitted congenital heart disease was excluded by echocardiography. Respiratory failure and need for oxygen secondary to respiratory obstruction due to glossoptosis are assumed. Transfontanelar ultrasound reveals grade II intraventricular hemorrhage, cystic image in the posterior fossa, megacisternal versus neuroepithelial cyst. At 47 days, he presented tonic-clonic seizures in the limbs opisthotonos and position of, he was treated with valproic acid, then Vigabatrina, with no response. Electroencephalographic trace shows discharge-suppression pattern. Develops infection associated with health care from respiratory origen, presents poor management of secretions and torpid evolution, dying at 110 days. The case is characterized by epileptic syndrome in a patient with a phenotype corresponding to Pierre Robin syndrome; but also has micropene. The presence of the three mentioned fatures could not be included in a previously described syndrome. In newborns with dysmorphia and seizures it is important to rule out the presence of structural alteration in the nervous system as responsible for the syndrome.

SCN2A mutation in an infant with Ohtahara syndrome and neuroimaging findings: expanding the phenotype of neuronal migration disorders

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first dayof life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.

Genetic analysis of Ohtahara syndrome and atypical benign partial epilepsy coexisting in a family / 中华实用儿科临床杂志

Objective To explore the genetic etiologies in 2 siblings with different epileptic encephalopathies (EEs) diagnosed as Ohtahara syndrome(OS) and atypical benign partial epilepsy(ABPE) from one family.Methods The 2 brothers were diagnosed at the Pediatric Neurological Clinic of Peking University First Hospital in September 2013,whose clinical data were collected.The coding region of the syntaxin-binding protein 1 gene (STXBP1) and glutamate receptor subunit gene (GRIN2A) were detected by using Sanger sequencing in the 2 siblings.For the elder brother,targeted next-generation sequencing was further performed to detect the genes associated with epilepsy.Results The younger brother manifested focal motor seizures and tonic spasms in cluster at the age of 1 month.Interictal electroencephalogram (EEG) showed suppression-burst pattern.He was diagnosed as OS.The elder brother had seizure onset at age of 6 years old.Focal motor seizure during sleep was his seizure type.His EEG showed interictal discharges in Rolandic area primarily.Electrical status epilepticus during sleep,epileptic negative myoclonus and intellectual disabilities occurred during the course.He was diagnosed as ABPE.Brain magnetic resonance imagines for both of them were normal.Screening of STXBP1 mutations for the younger brother found a de novo heterozygous mutation:c.1672C ＞ T (p.Q558X).Gene detection for the elder brother and the parents showed negative results.Conclusions Coexistence of distinct EEs was reported in 2 brother siblings:the younger brother had OS associated with a novel nonsense mutation in STXBP1,and the elder brother had ABPE without genetic evidence.This study indicated that different pathological mechanisms might exist underlying the two different EEs in a family.

Clinical features and gene mutations analysis in 62 children with early - onset epileptic encephalopathy of un-known causes / 中华实用儿科临床杂志

Objective To study the clinical features and gene mutations of early - onset epileptic encephalo-pathy(EOEE)of unknown causes and to identify pathogenic mutations of EOEE by next generation sequencing. Methods The clinical data of 62 cases diagnosed with unexplained EOEE between June 2013 and June 2015 were ob-tained and analyzed. Specimens were collected from the selected children and their parents. Next generation sequencing was used to detect epilepsy - related genes,and Sanger sequencing was performed to verify the results and confirm the source of the parents,further to identify suspected pathogenic mutations of EOEE. Results Among 62 cases with unex-plained EOEE,37 cases(61% )were diagnosed as non - specific EOEE,17 cases(27% )with West syndrome,6 ca-ses(10% )with Dravet syndrome,1 case(1% )with Ohtahara syndrome,1 case(1% )with early myoclonic epileptic encephalopathy. The pathogenic mutations were not detected among 17 cases with West syndrome and the early myoclonic epileptic encephalopathy. Among 37 cases with non - specific EOEE,suspected pathogenic mutations were detected in 7 cases. Three cases of missense mutations for PCDH19 gene,1 case of frame - shift mutation and 1 case of splice site mutation for CDKL5 gene,1 case of denovo nonsense mutation for KCNQ2 gene,and 1 case of missense muta-tion for GRIN2A gene were detected. Among 6 children with Dravet syndrome,2 cases of frame - shift mutations and 1 case of missense mutation for SCN1A gene were detected,of which 2 cases were of frame - shift mutations,1 case was denovo mutation,1 case of missense mutation for SCN1A gene and 1 case of missense mutation for SCN1A combined with SCN9A gene were detected. One case of denovo nonsense mutation for STXBP1 gene was detected. After treatment, 22 cases with clinical seizures were under control,and 40 cases were out of control. Conclusions The clinical pheno-types for children with unexplained EOEE were varied. SCN1A,SCN9A,STXBP1,PCDH19,CDKL5,KCNQ2 and GRIN2A genes detected in China are in accordance with those reported internationally and some gene sites are denovo mutations which have not been reported. The SCN9A gene may be the new pathogenic mutation for Dravet syndrome. And the KCNQ2 gene nonsense mutation may be the lethal mutation.

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice / Desenvolvimentos recentes na genética das encefalopatias epilépticas da infância: impacto na prática clínica

Recent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs.

Os avanços recentes em genética molecular permitiram a descoberta de vários genes para encefalopatias epilépticas da infância (EEIs). À medida que o conhecimento sobre os genes associados a este grupo de doenças se desenvolve, torna-se evidente que as EEIs apresentam uma série de características genéticas específicas, o que influencia o uso do teste molecular para fins clínicos. Entre as EEIs, há a presença de acentuada heterogeneidade genética e alta frequência de mutações de novo. Assim, os principais objetivos deste trabalho de revisão são apresentar e discutir o conhecimento atual a respeito de i) novas descobertas em genética molecular das EEIs, ii) correlações fenótipo-genótipo nas diferentes formas de EEIs; e, mais importante, iii) o impacto desses novos achados genéticos na prática clínica. Acompanhando o texto, incluímos uma tabela contendo a lista de genes conhecidos atualmente como envolvidos na etiologia da EEIs.

Síndrome de Ohtahara asociado con fístula traqueoesofágica en ''H'' / Ohtahara syndrome associated with H-type tracheoesophageal fistula

Introducción. El síndrome de Ohtahara es una encefalopatía epiléptica infantil temprana, caracterizada por espasmos tónicos frecuentes, crisis parciales y, ocasionalmente, mioclonías. El electroencefalograma interictal muestra un patrón característico de descargas de puntas que alternan con fases de supresión de la actividad eléctrica cerebral (brote-supresión). Las manifestaciones clínicas inician habitualmente antes de los 20 días de vida extrauterina. Los pocos casos reportados en la literatura no mencionan malformaciones congénitas asociadas. Caso clínico. Documentamos el primer caso clínico de un lactante masculino de 6 meses de edad con síndrome de Ohtahara asociado con una fístula traqueoesofágica tipo ''H''. Conclusiones. La asociación del síndrome de Ohtahara con la fístula traqueoesofágica pareciera deberse a una presentación fortuita y no con relación al síndrome neurológico.

Background. Ohtahara syndrome is an early infantile epileptic encephalopathy characterized by frequent tonic spasms, partial seizures and occasional myoclonus. Interictal EEG characteristically shows a pattern of burst of spikes alternating with phases of suppression of brain electrical activity (''burst-suppression''). Clinical manifestations usually begin before 20 days of life. The few cases reported in the literature do not mention associated congenital malformations. Case report. We report the first case of a 6-month-old male infant with Ohtahara syndrome associated with H-type tracheoesophageal fistula. Conclusions. The association between Ohtahara syndrome and tracheoesophageal fistula may be due to a fortuitous presentation without any relationship with the neurological syndrome.

Anesthetic experience of a patient with Ohtahara syndrome: A case report / 대한마취과학회지

Ohtahara syndrome (OS) is a rare epileptic encephalopathy that is characterized by an abnormal electroencephalogram (EEG) and intractable seizures in the neonatal and early infantile period. The patient of this reported case was delivered normally at 39 weeks of gestation without any complication. One week after birth, seizures that were refractory to anticonvulsants started with repetitive clustered tonic spasms. The child had no abnormal findings on the initial laboratory investigations. But he was diagnosed with OS according to the frequent tonic spasms, an abnormal EEG pattern of suppression-burst and magnetic resonance imaging of cortical dysplasia. He was planned to undergo an operation for brain lesion. This report describes our experience with the general anesthetic management when we performed craniotomy and right hemispherotomy for a patient with OS.