RESUMEN
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
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Mapeo Cromosómico/métodos , Trastornos del Neurodesarrollo/genética , Biología de Sistemas/métodos , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Humanos , Neurobiología/métodos , NeuropsiquiatríaRESUMEN
OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.
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Epilepsia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto Joven , Estudios de Cohortes , Discapacidades del Desarrollo/genética , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Epilepsia/patología , Estudios de Asociación Genética , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , FenotipoRESUMEN
The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
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Epilepsia , Medicina de Precisión , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/terapia , Pruebas Genéticas , Humanos , Convulsiones/genética , SugestiónRESUMEN
STUDY OBJECTIVE: Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently administered intranasally or intravenously and is dosed lower. Therefore, we used conventional and instrumental variable approaches to examine the effectiveness of midazolam in a national out-of-hospital cohort. METHODS: This retrospective cohort study of adults with status epilepticus used the ESO Data Collaborative research dataset (January 1, 2019, to December 31, 2019). The exposures were the route and dose of midazolam. We performed hierarchical logistic regression and 2-stage least squares regression using agency treatment patterns as an instrument to examine our outcomes, rescue therapy, and ventilatory support. RESULTS: There were 7,634 out-of-hospital encounters from 657 EMS agencies. Midazolam was administered intranasally in 20%, intravenously in 46%, and intramuscularly in 35% of the encounters. Compared with intramuscular administration, intranasal midazolam increased (risk difference [RD], 6.5%; 95% confidence interval [CI], 2.4% to 10.5%) and intravenous midazolam decreased (RD, -11.1%; 95% CI, -14.7% to -7.5%) the risk of rescue therapy. The differences in ventilatory support were not statistically significant (intranasal RD, -1.5%; 95% CI, -3.2% to 0.3%; intravenous RD, -0.3%; 95% CI, -1.9% to 1.2%). Higher doses were associated with a lower risk of rescue therapy (RD, -2.6%; 95% CI, -3.3% to -1.9%) and increased ventilatory support (RD, 0.4%; 95% CI, 0.1% to 0.7%). The instrumental variable analysis yielded similar results, except that dose was not associated with ventilatory support. CONCLUSION: The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.
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Midazolam , Estado Epiléptico , Administración Intranasal , Adulto , Anticonvulsivantes/uso terapéutico , Hospitales , Humanos , Midazolam/uso terapéutico , Estudios Retrospectivos , Estado Epiléptico/tratamiento farmacológico , Estados UnidosRESUMEN
OBJECTIVE: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent. RESULTS: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures. SIGNIFICANCE: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.).
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Benzodiazepinas/administración & dosificación , Estado Epiléptico/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Benzodiazepinas/uso terapéutico , Niño , Diazepam/administración & dosificación , Diazepam/uso terapéutico , Relación Dosis-Respuesta a Droga , Humanos , Lorazepam/administración & dosificación , Lorazepam/uso terapéutico , Midazolam/administración & dosificación , Midazolam/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
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Calcineurina/genética , Epilepsia/genética , Mutación , Trastornos del Neurodesarrollo/genética , Transmisión Sináptica/fisiología , Adolescente , Adulto , Calcineurina/metabolismo , Niño , Preescolar , Estudios de Cohortes , Epilepsia/patología , Exoma/genética , Femenino , Humanos , Lactante , Recién Nacido , Síndrome de Lennox-Gastaut/patología , Masculino , Trastornos del Neurodesarrollo/patología , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Espasmos Infantiles/genética , Espasmos Infantiles/patología , Adulto JovenRESUMEN
The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.
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Anticonvulsivantes/administración & dosificación , Peso Corporal/efectos de los fármacos , Levetiracetam/administración & dosificación , Fenitoína/análogos & derivados , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/administración & dosificación , Adolescente , Adulto , Peso Corporal/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Fenitoína/administración & dosificación , Método Simple Ciego , Estado Epiléptico/fisiopatología , Resultado del Tratamiento , Adulto JovenRESUMEN
Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.
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Epilepsia/genética , Mutación , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Genes Dominantes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas Munc18/genética , Canal de Sodio Activado por Voltaje NAV1.2/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Canales de potasio activados por Sodio , Secuenciación del ExomaRESUMEN
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the â¼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
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Discapacidad Intelectual/genética , Mutación/genética , Espasmos Infantiles/genética , Trastornos Generalizados del Desarrollo Infantil , Estudios de Cohortes , Exoma/genética , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Síndrome de Lennox-Gastaut , Masculino , Tasa de Mutación , N-Acetilglucosaminiltransferasas/genética , Probabilidad , Receptores de GABA-A/genética , Espasmos Infantiles/fisiopatologíaRESUMEN
De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.
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Proteínas Portadoras/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Secuencia de Aminoácidos , Proteínas Portadoras/química , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Proteínas del Tejido Nervioso/químicaRESUMEN
Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, we describe the challenges faced, alternative approaches considered, and progress to date. Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.
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Revelación , Epilepsia/genética , Genómica , Proyectos de Investigación , Revelación/estadística & datos numéricos , Genómica/métodos , Genómica/estadística & datos numéricos , HumanosRESUMEN
The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.
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Lesiones Encefálicas/complicaciones , Modelos Animales de Enfermedad , Epilepsia/etiología , Investigación Biomédica Traslacional , Animales , Lesiones Encefálicas/clasificación , HumanosRESUMEN
Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.
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Epilepsia/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo U/genética , Heterocigoto , Discapacidad Intelectual/genética , Edad de Inicio , Agenesia del Cuerpo Calloso/genética , Sistema Nervioso Central/anomalías , Sistema Nervioso Central/patología , Deleción Cromosómica , Cromosomas Humanos Par 1 , Epilepsia/diagnóstico , Femenino , Variación Genética , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Riñón/anomalías , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Fenotipo , Empalme del ARN , Ribonucleoproteínas Nucleares Pequeñas/genética , Convulsiones/diagnóstico , Convulsiones/genéticaRESUMEN
Psychogenic nonepileptic seizures (PNES) are relatively common, accounting for 5-40% of visits to tertiary epilepsy centers. Inpatient video-electroencephalogram (vEEG) monitoring is the gold standard for diagnosis, but additional positive predictive tools are necessary given vEEG's relatively scarce availability. In this study, we investigated if the number of patient-reported allergies distinguishes between PNES and epilepsy. Excessive allergy-reporting, like PNES, may reflect somatization. Using electronic medical records, ICD-9 codes, and text-identification algorithms to search EEG reports, we identified 905 cases of confirmed PNES and 5187 controls with epilepsy but no PNES. Patients with PNES averaged more self-reported allergies than patients with epilepsy alone (1.93 vs. 1.00, p<0.001). Compared to those with no allergies, each additional allergy linearly increased the percentage of patients with PNES by 2.98% (R(2)=0.71) such that with ≥12 allergies, 12/28 patients (42.8%) had PNES compared to 349/3368 (11.6%) of the population with no allergies (odds ratio=6.49). This relationship remained unchanged with logistic regression analysis. We conclude that long allergy lists may help identify patients with PNES. We hypothesize that a tendency to inaccurately self-report allergies reflects a maladaptive externalization of psychologic distress and that a similar mechanism may be responsible for PNES in some patients with somatic symptom disorder.
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Epilepsia/diagnóstico , Hipersensibilidad/complicaciones , Trastornos Psicofisiológicos/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Electroencefalografía , Registros Electrónicos de Salud , Epilepsia/complicaciones , Epilepsia/psicología , Femenino , Humanos , Clasificación Internacional de Enfermedades , Masculino , Persona de Mediana Edad , Trastornos Psicofisiológicos/complicaciones , Trastornos Psicofisiológicos/psicología , Estudios Retrospectivos , Adulto JovenRESUMEN
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.
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Encéfalo/metabolismo , Epilepsia Refractaria/genética , Epilepsia Refractaria/patología , MicroARNs/metabolismo , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Adulto , Animales , Línea Celular Tumoral , Células Cultivadas , Corteza Cerebral/citología , Simulación por Computador , Femenino , Perfilación de la Expresión Génica , Hepatoblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Componente Principal , Ratas , Factores de Tiempo , Adulto JovenRESUMEN
Advances in epilepsy genetics have been rapid, and it is challenging for clinicians on the ground to keep pace with these advances. The International League Against Epilepsy (ILAE) Genetics Commission has thus crafted a new Genetic Literacy series targeted at busy clinicians. Our goal is to help provide a concise, accessible resource on epilepsy genetics for the busy, on-the-ground clinician so that he/she can apply that knowledge at point-of-care to help patients. This new series is grounded in educational theories and evidence to ensure that learning is effective and efficient. We hope that by promoting and encouraging continuing medical education in epilepsy genetics, this eventually translates to better patient management and therefore better patient health outcomes.
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Competencia Clínica/normas , Epilepsia/genética , Pruebas Genéticas/normas , Alfabetización en Salud/normas , Epilepsia/diagnóstico , Pruebas Genéticas/tendencias , Alfabetización en Salud/tendencias , Humanos , Sistemas de Atención de Punto/normas , Sistemas de Atención de Punto/tendenciasRESUMEN
OBJECTIVE: To examine the effectiveness of intramuscular (IM) midazolam versus intravenous (IV) lorazepam for the treatment of pediatric patients with status epilepticus (SE) in the prehospital care setting. METHODS: This multicenter clinical trial randomized patients diagnosed with SE to receive either IM midazolam or IV lorazepam administered by paramedics in the prehospital care setting. Included in this secondary analysis were only patients younger than 18 years of age. Evaluated were the associations of the treatment group (IM vs. IV) with the primary outcome, defined as seizure cessation prior to emergency department (ED) arrival, and with patient characteristics, time to important events, and adverse events. Descriptive statistics and 99% confidence intervals (CIs) were used for the analysis. RESULTS: Of 893 primary study subjects, 120 met criteria for this study (60 in each treatment group). There were no differences in important baseline characteristics or seizure etiologies between groups. The primary outcome was met in 41 (68.3%) and 43 (71.7%) of subjects in the IM and IV groups, respectively (risk difference [RD] -3.3%, 99% CI -24.9% to 18.2%). Similar results were noted for those younger than 11 years (RD -1.3%, 99% CI -25.7% to 23.1%). Time from initiating the treatment protocol was shorter for children who received IM midazolam, mainly due to the shorter time to administer the active treatment. Safety profiles were similar. SIGNIFICANCE: IM midazolam can be rapidly administered and appears to be safe and effective for the management of children with SE treated in the prehospital setting. The results must be interpreted in the context of the secondary analysis design and sample size of the study.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Lorazepam/administración & dosificación , Midazolam/administración & dosificación , Estado Epiléptico/tratamiento farmacológico , Administración Intravenosa/métodos , Adolescente , Técnicos Medios en Salud , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Protocolos Clínicos , Femenino , Humanos , Lactante , Inyecciones Intramusculares/métodos , Lorazepam/uso terapéutico , Masculino , Midazolam/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.