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BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE: To identify rare, causal CNV in patients with RE. METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.
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Neuronas Colinérgicas , Variaciones en el Número de Copia de ADN , Epilepsia Rolándica/genética , Predisposición Genética a la Enfermedad , Argentina , Femenino , Pruebas Genéticas , Humanos , India , Italia , Masculino , Sinapsis , Estados UnidosRESUMEN
A pregnant woman with new-onset type 1 diabetes and ketoacidosis delivered an infant at 28 weeks of gestation who died with multiple organ failure and severe cerebral vasculopathy with extensive hemorrhage, diffuse microgliosis, and edema. This illustrates that antenatal metabolic and inflammatory stressors may be associated with neonatal encephalopathy and cerebral hemorrhage.
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Encefalopatías/etiología , Cetoacidosis Diabética/complicaciones , Enfermedades del Prematuro/etiología , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Adulto , Autopsia , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Madres , Insuficiencia Multiorgánica/etiología , Embarazo , Complicaciones del EmbarazoRESUMEN
OBJECTIVE: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. METHODS: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.
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Dislexia/epidemiología , Dislexia/fisiopatología , Epilepsia Rolándica/epidemiología , Epilepsia Rolándica/fisiopatología , Lectura , Hermanos , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Dislexia/diagnóstico , Electroencefalografía/métodos , Epilepsia Rolándica/diagnóstico , Familia , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
To determine whether asymmetric macrosomia (disproportionately large body size in comparison to head circumference) could be demonstrated in a population of infants suffering shoulder dystocia during delivery relative to those that did not suffer from shoulder dystocia. A case-control study was conducted as a retrospective chart review over 3 years at a large maternity hospital in an urban setting. Among infants over 4,000 g, those that suffered from shoulder dystocia during delivery had a smaller mean head circumference than infants of a similar size that did not suffer from shoulder dystocia. A statistically significant difference was also present when cases of documented gestational diabetes were excluded. Asymmetric macrosomia is more likely to be present in a population of infants who suffered shoulder dystocia during delivery. This knowledge could be used in designing tools to predict which pregnancies are at highest risk for shoulder dystocia during delivery.
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Cefalometría , Distocia/epidemiología , Macrosomía Fetal/epidemiología , Hombro , Plexo Braquial/lesiones , Estudios de Casos y Controles , Desproporción Cefalopelviana , Diabetes Gestacional/epidemiología , Femenino , Humanos , Recién Nacido , Embarazo , Estudios Retrospectivos , Rhode Island/epidemiología , Factores de Riesgo , Población Urbana , Extracción Obstétrica por Aspiración/estadística & datos numéricosRESUMEN
The ketogenic diet remains one of the most effective treatments for medically refractory childhood epilepsy. In spite of the long history of its use, relatively little is known about the mechanism of action. The diet's efficacy in a wide range of epilepsy syndromes suggests that it may have multiple mechanisms of action, each of which may be more relevant to a specific disease state. Further research is necessary to define the mechanism of action, which may, in turn, lead to easier means to provide the therapeutic benefit.
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Dieta Cetogénica , Epilepsias Mioclónicas/dietoterapia , Preescolar , Dieta Cetogénica/efectos adversos , Dieta Cetogénica/métodos , Humanos , MasculinoRESUMEN
Artist-critic Clive James said: "Common sense and a sense of humor are the same thing, moving at different speeds. A sense of humor is just common sense, dancing. Those who lack humor are without judgment and should be trusted with nothing."
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AIM: Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and/or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non-convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study. METHOD: We examined 57 children (42 females, 15 males), aged 6 to 17 years (mean 10y 1mo, SD 2y 9mo), with new-onset, idiopathic epilepsy, using tests of cognitive function reflective of new learning, memory, and attention. Seizures were classified as generalized convulsive (n=5), generalized non-convulsive (n=18), or focal (n=34). Focal seizures were divided into unilateral versus bilateral independent foci, and presence versus absence of secondary generalization. RESULTS: Attention was a particular area of weakness across all groups. The Vocabulary score of an intelligence screen was higher for the focal seizure groups (p=0.012), primarily because of a difference between the unilateral focal and the primary generalized groups (p<0.047). Children with generalized, non-convulsive seizures performed significantly worse than the focal group on a measure of short-term auditory memory (p=0.019). All groups performed poorly on a test of visual-motor speed. INTERPRETATION: These findings suggest intrinsic abnormalities in children with new-onset, idiopathic epilepsy at baseline.
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Trastornos de la Conducta Infantil/diagnóstico , Trastornos del Conocimiento/diagnóstico , Epilepsias Parciales/diagnóstico , Epilepsia Generalizada/diagnóstico , Trastornos de la Destreza Motora/diagnóstico , Pruebas Neuropsicológicas/estadística & datos numéricos , Determinación de la Personalidad/estadística & datos numéricos , Adolescente , Niño , Trastornos de la Conducta Infantil/psicología , Trastornos del Conocimiento/psicología , Femenino , Humanos , Inteligencia , Masculino , Trastornos de la Destreza Motora/psicología , Psicometría/estadística & datos numéricos , Reproducibilidad de los ResultadosRESUMEN
In September 2017, the Child Neurology Society (CNS) convened a special task force to review the practice of child neurology in the United States. This was deemed a necessity by our membership, as our colleagues expressed discouragement and burnout by the increase in workload without additional resources; reliance on work relative value units (wRVUs) as the sole basis of compensation; a push by administrators for providers to see more patients with less allotted time; and lack of administrative, educational, and research support. The CNS Task Force designed and distributed a survey to multiple academic divisions of various sizes, as well as to private practices. Our findings were strikingly similar across different practices, demonstrating high workloads, lack of resources, poor electronic medical record support, and high provider symptoms of fatigue and burnout. From the results, the CNS Task Force has concluded that wRVUs cannot be the sole basis of compensation for child neurology. We have also made several specific recommendations for alleviating the current situation, including innovative ways to fund child neurology as well as ways to enhance job satisfaction.
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Neurología/economía , Pediatría/economía , Escalas de Valor Relativo , HumanosRESUMEN
OBJECTIVE: As treatment options for epilepsy have increased, there has been a commensurate increase in interest in the side effect profiles of these drugs. METHODS: In this study, children between the ages of 6 and 17 with a diagnosis of new-onset, idiopathic epilepsy were evaluated at baseline (n=57) and 6 (n=45) and 12 (n=31) months after initiation of antiepileptic drug therapy. RESULTS: There was improvement in the cognitive functioning of children after 12 months of treatment. A transient drop in performance of children with generalized seizures (10 of 11 of whom had absence seizures) at 6 months may have been due to persistent seizures, the drugs used to treat them (predominantly ethosuximide), or both. Worsening of reaction time and reaction time variability in the focal seizure group, the only scores showing persistent deterioration over 12 months, may be attributable to the medications used for this group, the most common of which was carbamazepine. CONCLUSIONS: There were few adverse effects of antiepileptic drug treatment in the group followed over 12 months. Carbamazepine may have been responsible for persistent impairment of reaction time and reaction time variability.
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Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Cognición/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Conducta Verbal/efectos de los fármacos , Adolescente , Análisis de Varianza , Anticonvulsivantes/efectos adversos , Niño , Epilepsia/clasificación , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Inteligencia , Masculino , Pruebas Neuropsicológicas , Tiempo de Reacción/efectos de los fármacos , Estudios Retrospectivos , Factores de TiempoRESUMEN
The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer disease, Parkinson disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, anecdotal data and the high level of interest in this treatment must not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure. This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure and is combined with an illustration of the neuropathologic findings in a fatal case of cannabis-induced psychosis. The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if subsets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis.
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Encéfalo/efectos de los fármacos , Cannabinoides/efectos adversos , Cannabinoides/uso terapéutico , Cannabis/efectos adversos , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Encéfalo/fisiopatología , Resultado Fatal , Humanos , Masculino , Abuso de Marihuana/patología , Abuso de Marihuana/fisiopatología , Persona de Mediana Edad , Psicosis Inducidas por Sustancias/patología , Psicosis Inducidas por Sustancias/fisiopatologíaRESUMEN
OBJECTIVE: Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case-control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. METHODS: We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. RESULTS: Homozygosity at the T allele of SNP rs662702 in the 3' untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20-47.22), P = 2.6 × 10(-4) and is seen in 3.9% of cases but only 0.3% of controls. INTERPRETATION: The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.
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PURPOSE: This Children's Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Glioma/tratamiento farmacológico , Adolescente , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/radioterapia , Carboplatino/administración & dosificación , Niño , Preescolar , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Glioma/radioterapia , Humanos , Masculino , Terapia Neoadyuvante , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
In a retrospective study of 59 children (ages 9 months to 23 years; mean age 11 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of levetiracetam therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications (range 0-5), and the number of previous anticonvulsant drugs (range 1-12). Good to excellent seizure control (50-100% reduction) was attained in 6 (40%) patients with focal seizures, 16 (55%) patients with generalized seizures, and 8 (61%) patients with mixed seizures; these efficacy rates were not significantly different. The efficacy of levetiracetam was independent of cognitive status. Adverse effects were not associated with higher mean doses. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of levetiracetam and zonisamide had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of the mechanisms of action of levetiracetam and zonisamide and/or their pharmacodynamic interactions.
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Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Epilepsia Generalizada/tratamiento farmacológico , Piracetam/análogos & derivados , Adolescente , Adulto , Anticonvulsivantes/administración & dosificación , Niño , Preescolar , Cognición , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Epilepsias Parciales/psicología , Epilepsia Generalizada/psicología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Isoxazoles/administración & dosificación , Levetiracetam , Masculino , Piracetam/administración & dosificación , Piracetam/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , ZonisamidaRESUMEN
In a retrospective study of 35 children (ages 8 months to 22 years; mean age 9 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of zonisamide therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications, and the number of previous anticonvulsant drugs. Good to excellent seizure control (50-100% reduction) was attained in seven (54%) patients with generalized seizures, two (40%) patients with focal seizures, five (35%) patients with mixed seizures, and one (33%) patient with infantile spasms. In this group of children, the efficacy of zonisamide was comparable for focal, generalized, and mixed seizures. The efficacy of zonisamide was independent of cognitive status. Adverse effects were not associated with a higher mean dose. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of zonisamide and levetiracetam had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of mechanisms of action of zonisamide and levetiracetam and/or their pharmacodynamic interactions.