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N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.
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Epilepsia , Receptores de N-Metil-D-Aspartato , Niño , Humanos , Epilepsia/genética , Mutación Missense , Fenotipo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: The objective of the study was to localize sources of interictal high-frequency activity (HFA), from tripolar electroencephalography (tEEG), in patient-specific, realistic head models. METHODS: Concurrent electroencephalogram (EEG) and tEEG were recorded from nine patients undergoing video-EEG, of which eight had seizures during the recordings and the other had epileptic activity. Patient-specific, realistic boundary element head models were generated from the patient's magnetic resonance images (MRIs). Forward and inverse modeling was performed to localize the HFA to cortical surfaces. RESULTS: In the present study, performed on nine patients with epilepsy, HFA observed in the tEEG was localized to the surface of subject-specific, realistic, cortical models, and found to occur almost exclusively in the seizure onset zone (SOZ)/irritative zone (IZ). SIGNIFICANCE: High-frequency oscillations (HFOs) have been studied as precise biomarkers of the SOZ in epilepsy and have resulted in good therapeutic effect in surgical candidates. Knowing where the sources of these highly focal events are located in the brain can help with diagnosis. High-frequency oscillations are not commonly observed in noninvasive EEG recordings, and invasive electrocorticography (ECoG) is usually required to detect them. However, tEEG, i.e., EEG recorded on the scalp with tripolar concentric ring electrodes (TCREs), has been found to detect narrowband HFA from high gamma (approximately 80â¯Hz) to almost 400â¯Hz that correlates with SOZ diagnosis. Thus, source localization of HFA in tEEG may help clinicians identify brain regions of the epileptic zone. At the least, the tEEG HFA localization may help determine where to perform intracranial recordings used for precise diagnosis.
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Encéfalo/fisiopatología , Epilepsia/diagnóstico , Convulsiones/diagnóstico , Encéfalo/diagnóstico por imagen , Encéfalo/cirugía , Mapeo Encefálico/métodos , Electrocorticografía , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Convulsiones/diagnóstico por imagen , Convulsiones/fisiopatologíaRESUMEN
Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.
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Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Feto/fisiología , Interleucina-6/antagonistas & inhibidores , Daño por Reperfusión/tratamiento farmacológico , Animales , Barrera Hematoencefálica/fisiopatología , Western Blotting , Isquemia Encefálica/fisiopatología , Proteínas Portadoras/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Femenino , Feto/efectos de los fármacos , Interleucina-6/inmunología , Interleucina-6/metabolismo , Proteínas de la Membrana/metabolismo , Embarazo , Daño por Reperfusión/fisiopatología , Ovinos , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1ß monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1ß protein. This antibody also neutralizes the effects of interleukin-1ß protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1ß monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24h of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1ß antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154M NaCl) or anti-interleukin-1ß monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4h after ischemia. Concentrations of interleukin-1ß protein and anti-interleukin-1ß monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1ß protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1ß protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1ß monoclonal antibody infusions, plasma anti-interleukin-1ß monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1ß monoclonal antibody levels were higher (P<0.03), and interleukin-1ß protein concentrations (P<0.03) and protein expressions (P<0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion-related increases in Ki across the brain regions (P<0.04), and Ki showed an inverse linear correlation (r= -0.65, P<0.02) with anti-interleukin-1ß monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1ß monoclonal antibody infusions after ischemia result in brain anti-interleukin-1ß antibody uptake, and attenuate ischemia-reperfusion-related interleukin-1ß protein up-regulation and increases in blood-brain barrier permeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1ß, contributes to impaired blood-brain barrier function after ischemia in the fetus.
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Anticuerpos Neutralizantes/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Hipoxia Fetal/tratamiento farmacológico , Hipoxia Fetal/patología , Interleucina-1beta/inmunología , Animales , Anticuerpos Neutralizantes/farmacología , Presión Sanguínea/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Encéfalo/embriología , Encéfalo/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Estenosis Carotídea/complicaciones , Citocinas/metabolismo , Modelos Animales de Enfermedad , Embrión de Mamíferos , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipoxia Fetal/etiología , Frecuencia Cardíaca Fetal/efectos de los fármacos , Interleucina-1beta/metabolismo , Ratones , Embarazo , Flujo Sanguíneo Regional/efectos de los fármacos , Ovinos , Proteínas de Uniones Estrechas/metabolismoRESUMEN
We compared the epilepsy phenotypes in children with genetically defined versus undefined autism spectrum disorder (ASD). A single-center retrospective study was conducted to investigate diagnostic yields of different genetic testing for children with ASD. Patients with at least one testing modality were included and classified as having genetically defined ASD or not based on updated genotype-phenotype correlation. Of the 523 patients included, 79 (15.1%) had results explaining their ASD diagnosis. WES (whole exome sequencing) outperformed CMA (chromosomal microarray) on diagnostic yield (23.0% versus 8.3%). Compared to those with non-diagnostic test(s), children with genetically defined ASD were associated with higher rates for microcephaly, hypotonia, dysmorphic features, and developmental delay/regression. The prevalence of epilepsy was significantly higher in children with genetically defined ASD than those without a genetic diagnosis (35.4% versus 16.4%, p < 0.001, power = 0.97). Furthermore, children with genetically defined ASD had a younger age of epilepsy onset (median 2.2 versus 5.0 years, p = 0.002, power = 0.90) and a higher rate of drug-resistant epilepsy although not reaching statistical significance (35.7% versus 21.9%, p = 0.20). Our study has provided further evidence to support WES as first-tier test for children with ASD and that an early genetic diagnosis has the potential to inform further surveillance and management for ASD comorbid conditions including epilepsy.
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OBJECTIVE: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial. METHODS: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc. RESULTS: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints. INTERPRETATION: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure.
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Anticonvulsivantes , Epilepsias Parciales , Niño , Humanos , Preescolar , Lacosamida/uso terapéutico , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/tratamiento farmacológico , Reproducibilidad de los Resultados , Resultado del Tratamiento , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , ElectroencefalografíaRESUMEN
We report on a pedigree with a pair of brothers each with minor anomalies, developmental delay, and autistic-symptoms who share an unbalanced translocation (not detectable by karyotype). The unbalanced translocation involves a 7.1 Mb loss of the terminal portion of 10q, and a 4.2 Mb gain of 11q. One of the brothers also developed a cerebellar juvenile pilocytic astrocytoma. The father was found to be a balanced carrier and the couple had a previous miscarriage. We demonstrate that the breakpoint for the triplicated region from chromosome 11 is adjacent to two IgLON genes, namely Neurotrimin (NTM) and Opioid Binding Protein/Cell Adhesion Molecule-like (OPCML). These genes are highly similar neural cell adhesion molecules that have been implicated in synaptogenesis and oncogenesis, respectively. The children also have a 10q deletion and are compared to other children with the 10q deletion syndrome which generally does not involve autism spectrum disorders (ASDs) or cancer. Together these data support a role for NTM and OPCML in developmental delay and potentially in cancer susceptibility.
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Astrocitoma/genética , Neoplasias Cerebelosas/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Deleción Cromosómica , Translocación Genética , Trisomía , Astrocitoma/diagnóstico , Neoplasias Cerebelosas/diagnóstico , Niño , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Preescolar , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 11 , Hibridación Genómica Comparativa , Proteínas del Citoesqueleto , Humanos , Hibridación Fluorescente in Situ , Cariotipo , Masculino , Linaje , Proteínas/genéticaRESUMEN
Autism spectrum disorder (ASD) with regression (ASD-R) involves the loss of previously attained developmental milestones, typically during the first or second year of life. As children age, it is not uncommon for them to develop comorbid conditions such as aggressive behaviors or epilepsy, which can inhibit habilitation in language and social function. In this paper, we hypothesize that aggressive behaviors and epilepsy more commonly develop in patients with ASD-R than in those without a history of regression (ASD-NR). We conducted a retrospective review of non-syndromic patients with ASD over 12 years of age and compared the rates of epilepsy and aggression between ASD-R and ASD-NR patients. Patients with ASD-R, as compared to ASD-NR patients, demonstrated non-significantly higher rates of epilepsy (51.8% vs. 38.1%, p = 0.1335) and aggressive behaviors (73.2% vs. 57.1%, p = 0.0673) when evaluated separately. The rates for combined epilepsy and aggression, however, were statistically significant when comparing ASD-R versus ASD patients (44.5% vs. 23.8%, p = 0.0163). These results suggest that epilepsy with aggression is more common in ASD-R as compared to ASD-NR patients. When considering the impact of epilepsy and aggression on quality of life, these co-morbidities effectively cause a second regression in patients who experienced an earlier regression as toddlers. A larger, prospective trial is recommended to confirm these associations and further define the timeline in which these characteristics develop from early childhood to adolescence.
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Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD), there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an online survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities, potential etiologies, and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic-clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood, while surgery and the Atkins/modified Atkins Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but nonetheless, these data provide insights into novel relationships that may assist in a better understanding of epilepsy in ASD and provide insight into personalizing epilepsy care in ASD.
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The BRAIN Foundation (Pleasanton, CA) hosted Synchrony 2022, a medical conference focusing on research for treatments to benefit individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) [...].
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The BRAIN Foundation (Pleasanton, CA, USA) hosted Synchrony 2022, a translational medicine conference focused on research into treatments for individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) [...].
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Trastorno del Espectro Autista/terapia , Anomalías Craneofaciales/terapia , Estimulación Encefálica Profunda/métodos , Cardiopatías Congénitas/terapia , Discapacidad Intelectual/terapia , Trastorno del Espectro Autista/etiología , Deleción Cromosómica , Cromosomas Humanos Par 9 , Anomalías Craneofaciales/complicaciones , Femenino , Cardiopatías Congénitas/complicaciones , Humanos , Discapacidad Intelectual/complicacionesRESUMEN
PURPOSE: Neuromodulation holds great promise for the treatment of drug-resistant epilepsy. This article reviews the most common types of neuromodulation as well as potential future applications of preclinical techniques such as optogenetics. This review serves as a reference for treating neurologists on the latest science behind such treatment approaches. METHODS: This narrative review briefly describes the preclinical and clinical history of each technique, with a special emphasis on, wherever possible, strong clinical evidence and any available data from pediatric populations. A detailed literature review was performed for each method of neuromodulation. FINDINGS: Since the concept of electrical stimulation as a treatment for neurologic conditions emerged in the early 19th century, neuromodulatory techniques using direct or induced electrical currents have been developed to reduce seizure frequency and duration in patients with drug-resistant epilepsy. This article reviews the applications, clinical guidelines, outcomes, and proposed mechanisms of available approaches, including vagus nerve stimulation, responsive neurostimulation, deep brain stimulation, and transcranial stimulation. Although promising outcomes have been achieved in adults and children with drug-resistant epilepsy, heterogeneity among epilepsy types and etiologies, optimization of stimulation parameters, and a lack of direct comparisons between neuromodulatory approaches are challenges that have yet to be overcome. IMPLICATIONS: Neuromodulation is a rapidly evolving field in clinical neuroscience that has treatment implications in a variety of clinical arenas, with epilepsy among the most important of those. It offers the promise of delivering effective treatment for drug-resistant epilepsy, with potentially fewer side effects than standard surgical approaches. © 2020 Elsevier HS Journals, Inc.
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Terapia por Estimulación Eléctrica , Epilepsia/terapia , Animales , HumanosRESUMEN
Autism spectrum disorder (ASD) is a multifactorial, pervasive neurodevelopmental disorder defined by the core symptoms of significant impairment in social interaction and communication as well as restricted, repetitive patterns of behavior. In addition to these core behaviors, persons with ASD frequently have associated noncore behavioral disturbance (ie, self-injury, aggression), as well as several medical comorbidities. Currently, no effective treatment exists for the core symptoms of ASD. This review reports the available preclinical and clinical data regarding the use of cannabis and cannabidiol in the treatment of core symptoms, noncore symptoms and comorbidities associated with ASD. Additionally, we describe our clinical experience working with children and young adults with ASD who have used cannabis or cannabidiol. At present, preclinical and clinical data suggest a potential for therapeutic benefit among some persons with ASD and that it is overall well tolerated. Further research is required to better identify patients who may benefit from treatment without adverse effects.
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Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/fisiopatología , Moduladores de Receptores de Cannabinoides/farmacología , Marihuana Medicinal/farmacología , Adolescente , Adulto , Animales , Trastorno del Espectro Autista/epidemiología , Niño , Preescolar , Comorbilidad , Humanos , Adulto JovenRESUMEN
PURPOSE OF REVIEW: This article provides an overview of the most common nervous system malformations and serves as a reference for the latest advances in diagnosis and treatment. RECENT FINDINGS: Major advances have occurred in recognizing the genetic basis of nervous system malformations. Environmental causes of nervous system malformations, such as perinatal infections including Zika virus, are also reviewed. Treatment for nervous system malformations begins prior to birth with prevention. Folic acid supplementation reduces the risk of neural tube defects and is an important part of health maintenance for pregnant women. Fetal surgery is now available for prenatal repair of myelomeningocele and has been demonstrated to improve outcomes. SUMMARY: Each type of nervous system malformation is relatively uncommon, but, collectively, they constitute a large population of neurologic patients. The diagnosis of nervous system malformations begins with radiographic characterization. Genetic studies, including chromosomal microarray, targeted gene sequencing, and next-generation sequencing, are increasingly important aspects of the assessment. A genetic diagnosis may identify an associated medical condition and is necessary for family planning. Treatment consists primarily of supportive therapies for developmental delays and epilepsy, but prenatal surgery for myelomeningocele offers a glimpse of future possibilities. Prognosis depends on multiple clinical factors, including the examination findings, imaging characteristics, and genetic results. Treatment is best conducted in a multidisciplinary setting with neurology, neurosurgery, developmental pediatrics, and genetics working together as a comprehensive team.
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Malformaciones del Sistema Nervioso , Adulto , Sistema Nervioso Central/embriología , Femenino , Humanos , Recién Nacido , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/terapia , Neurogénesis/fisiología , EmbarazoAsunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Estado Epiléptico/diagnóstico , Estado Epiléptico/virología , COVID-19 , Niño , Infecciones por Coronavirus/terapia , Humanos , Masculino , Pandemias , Neumonía Viral/terapia , SARS-CoV-2 , Estado Epiléptico/terapiaRESUMEN
Pro-inflammatory cytokines contribute to hypoxic-ischemic brain injury. Blood-brain barrier (BBB) dysfunction represents an important component of hypoxic-ischemic brain injury in the fetus. Hypoxic-ischemic injury could accentuate systemic cytokine transfer across the fetal BBB. There has been considerable conjecture suggesting that systemic cytokines could cross the BBB during the perinatal period. Nonetheless, evidence to support this contention is sparse. We hypothesized that ischemia-reperfusion increases the transfer of systemic interleukin-1ß (IL-1ß) across the BBB in the fetus. Ovine fetuses at 127 days of gestation were studied 4 hours after 30 minutes of bilateral carotid artery occlusion and compared with a nonischemic group. Recombinant ovine IL-1ß protein was expressed from an IL-1ß pGEX-2 T vector in E. coli BL-21 cells and purified. The BBB function was quantified in 12 brain regions using a blood-to-brain transfer constant with intravenous (125)I-radiolabeled IL-1ß ((125)I-IL-1ß). Interleukin-1ß crossed the intact BBB in nonischemic fetuses. Blood-to-brain transport of (125)I-IL-1ß was higher (P<0.05) across brain regions in fetuses exposed to ischemia-reperfusion than nonischemic fetuses. We conclude that systemic IL-1ß crosses the intact fetal BBB, and that ischemia-reperfusion increases transfer of this cytokine across the fetal BBB. Therefore, altered BBB function after hypoxia-ischemia facilitates entry of systemic cytokines into the brain of the fetus.
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Barrera Hematoencefálica/metabolismo , Hipoxia Fetal/metabolismo , Feto/metabolismo , Hipoxia Encefálica/metabolismo , Interleucina-1beta/metabolismo , Animales , Transporte Biológico Activo , Barrera Hematoencefálica/patología , Femenino , Hipoxia Fetal/patología , Feto/patología , Hipoxia Encefálica/patología , EmbarazoRESUMEN
BACKGROUND: Status epilepticus (SE) encompasses a wide range of seizure types with different clinical presentations, pathophysiologies, treatment imperatives, and outcomes. The most dramatic and life-threatening form, generalized convulsive status epilepticus, has been reviewed in all of these aspects, but other less common types of SE have been described less extensively. REVIEW SUMMARY: Definitions of generalized convulsive SE and its pathophysiology are reviewed briefly. Defining SE by a specific duration of seizures is controversial and has implications for studies and for clinical management. Several types of SE are different in their causes, presentations, and outcomes. Many are underdiagnosed. This article focuses on the pharmacology and clinical studies of several anticonvulsant medications used to treat SE. A protocol approach is not detailed. Rather, the clinical evaluation begins with meticulous diagnosis of the type of SE. Establishing the SE syndrome diagnosis and use of anticonvulsants with demonstrated effectiveness facilitate an appropriate treatment plan for individual patients. Recent developments in the basic science of SE raise the possibility of better treatments in the future. CONCLUSIONS: As there are many types of seizures, there are also many types of SE. Each has unique presentations and treatment considerations. Review of actual clinical data from SE treatment studies should be helpful in devising the best treatment for an individual patient.
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Estado Epiléptico/diagnóstico , Estado Epiléptico/terapia , Anticonvulsivantes/uso terapéutico , Resistencia a Medicamentos , Humanos , Estado Epiléptico/clasificación , Estado Epiléptico/fisiopatología , Terminología como AsuntoRESUMEN
Since the advent of MR imaging, cortical malformations have become an increasingly recognized cause of epilepsy and neurologic impairment. Improved radiographic characterization of cortical malformations has been requisite to defining their genetics, and a large portion of these disorders are now known to have a genetic basis. Uncovering genetic etiologies has provided insight into phenotypic diversity, revealed the importance of de novo mutations, and resulted in improved radiographic-genetic correlation. This article provides an overview of major cerebral cortical malformations and focuses on the genetic mechanisms of their causation.