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1.
J ECT ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968441

RESUMO

ABSTRACT: This is the first report of pediatric catatonia syndrome in MED13L haploinsufficiency syndrome. This report describes unique challenges in diagnosis and management of catatonia in rare genetic conditions. The case also illustrates the use of electroconvulsive therapy in patients with epilepsy, epileptic encephalopathy, or other epileptic diathesis and the clinical conundrum in determining the course of maintenance electroconvulsive therapy.

2.
Epilepsia Open ; 9(1): 333-344, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38071463

RESUMO

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. METHODS: We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. RESULTS: We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%-46%] for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. SIGNIFICANCE: No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. PLAIN LANGUAGE SUMMARY: Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk-between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.


Assuntos
Epilepsia , Convulsões , Humanos , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Tomada de Decisões , Preferência do Paciente , Pacientes
3.
Ann Neurol ; 95(4): 754-759, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38113311

RESUMO

OBJECTIVE: De novo mutations of the voltage-gated sodium channel gene SCN8A cause developmental and epileptic encephalopathy (DEE). Most pathogenic variants result in gain-of-function changes in activity of the sodium channel Nav1.6, poorly controlled seizures, and significant comorbidities. In previous work, an antisense oligonucleotide (ASO) reduced Scn8a transcripts and increased lifespan after neonatal administration to a mouse model. Here, we tested long-term ASO treatment initiated after seizure onset, as required for clinical application. METHODS: ASO treatment was initiated after observation of a convulsive seizure and repeated at 4 to 6 week intervals for 1 year. We also tested the long-term efficacy of an AAV10-short hairpin RNA (shRNA) virus administered on P1. RESULTS: Repeated treatment with the Scn8a ASO initiated after seizure onset provided long-term survival and reduced seizure frequency during a 12 month observation period. A single treatment with viral shRNA was also protective during 12 months of observation. INTERPRETATION: Downregulation of Scn8a expression that is initiated after the onset of seizures is effective for long-term treatment in a model of SCN8A-DEE. Repeated ASO administration or a single dose of viral shRNA prevented seizures and extended survival through 12 months of observation. ANN NEUROL 2024;95:754-759.


Assuntos
Epilepsia , Animais , Camundongos , Modelos Animais de Doenças , Regulação para Baixo/genética , Epilepsia/terapia , Epilepsia/tratamento farmacológico , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Convulsões/genética , Canais de Sódio/genética
4.
Ann Neurol ; 94(5): 812-824, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37606181

RESUMO

OBJECTIVES: DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions. METHODS: Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice. RESULTS: Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic-clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. INTERPRETATION: Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023;94:812-824.


Assuntos
Epilepsias Parciais , Epilepsia , Morte Súbita Inesperada na Epilepsia , Animais , Camundongos , Apneia/complicações , Morte Súbita/etiologia , Morte Súbita/prevenção & controle , Epilepsias Parciais/complicações , Proteínas Ativadoras de GTPase/genética , Convulsões/complicações
5.
Epilepsia Open ; 8(2): 371-385, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36693718

RESUMO

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in patients with epilepsy who become seizure-free. Little is known about how discontinuation decisions are being made in practice. We measured the frequency of, and factors associated with, discussions and decisions surrounding ASM discontinuation. METHODS: We performed a multicenter retrospective cohort study at the University of Michigan (UM) and two Dutch centers: Wilhelmina Children's Hospital (WCH) and Stichting Epilepsie Instellingen Nederland (SEIN). We screened all children and adults with outpatient epilepsy visits in January 2015 and included those with at least one visit during the subsequent 2 years where they were seizure-free for at least one year. We recorded whether charts documented (1) a discussion with the patient about possible ASM discontinuation and (2) any planned attempt to discontinue at least one ASM. We conducted multilevel logistic regressions to determine factors associated with each outcome. RESULTS: We included 1058 visits from 463 patients. Of all patients who were seizure-free at least one year, 248/463 (53%) had documentation of any discussion and 98/463 (21%) planned to discontinue at least one ASM. Corresponding frequencies for patients who were seizure-free at least 2 years were 184/285 (65%) and 74/285 (26%). The probability of discussing or discontinuing increased with longer duration of seizure freedom. Still, even for patients who were 10 years seizure-free, our models predicated that in only 49% of visits was a discontinuation discussion documented, and in only 16% of visits was it decided to discontinue all ASMs. Provider-to-provider variation explained 18% of variation in whether patients discontinued any ASM. SIGNIFICANCE: Only approximately half of patients with prolonged seizure freedom had a documented discussion about ASM discontinuation. Discontinuation was fairly rare even among low-risk patients. Future work should further explore barriers to and facilitators of counseling and discontinuation attempts.


Assuntos
Epilepsia , Estado Epiléptico , Criança , Adulto , Humanos , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Risco
6.
Brain Commun ; 5(6): fcad283, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38425576

RESUMO

Voltage-gated sodium channel ß1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding ß1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b-/- mice. ß1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, ß1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of ß1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.

7.
JAMA Neurol ; 79(12): 1267-1276, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36315135

RESUMO

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.


Assuntos
Epilepsia , Testes Genéticos , Humanos , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Estudos Transversais , Testes Genéticos/métodos , Epilepsia/tratamento farmacológico , Epilepsia/genética , Convulsões/genética
8.
Epilepsia ; 63(12): e156-e163, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36161652

RESUMO

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) are ligand-gated cationic channels formed from combinations of GluA1-4 subunits. Pathogenic variants of GRIA1-4 have been described in patients with developmental delay, intellectual disability, autism spectrum disorder, and seizures, with GRIA2 variants typically causing AMPAR loss of function. Here, we identify a novel, heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V, NM_001083619.1) in a 1-year-old boy with epilepsy, developmental delay, and failure to thrive. We made patch-clamp recordings to compare the functional and pharmacological properties of variant and wild-type receptors expressed in HEK293 cells, with and without the transmembrane AMPAR regulatory protein γ2. This showed GluA2 A643V-containing AMPARs to exhibit a novel gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity. Perampanel, an antiseizure AMPAR negative allosteric modulator, was able to fully block GluA2 A643V/γ2 currents, suggesting potential therapeutic efficacy. The subsequent introduction of perampanel to the patient's treatment regimen was associated with a marked reduction in seizure burden, a resolution of failure to thrive, and clear developmental gains. Our study reveals that GRIA2 disorder can be caused by a gain-of-function variant, and both predicts and suggests the therapeutic efficacy of perampanel. Perampanel may prove beneficial for patients with other gain-of-function GRIA variants.


Assuntos
Transtorno do Espectro Autista , Insuficiência de Crescimento , Humanos , Lactente , Mutação com Ganho de Função , Células HEK293 , Convulsões/tratamento farmacológico , Convulsões/genética
9.
Epilepsia ; 63(10): e125-e131, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35892317

RESUMO

Voltage-gated sodium and potassium channels regulate the initiation and termination of neuronal action potentials. Gain-of-function mutations of sodium channel Scn8a and loss-of-function mutations of potassium channels Kcna1 and Kcnq2 increase neuronal activity and lead to seizure disorders. We tested the hypothesis that reducing the expression of Scn8a would compensate for loss-of-function mutations of Kcna1 or Kcnq2. Scn8a expression was reduced by the administration of an antisense oligonucleotide (ASO). This treatment lengthened the survival of the Kcn1a and Kcnq2 mutants, and reduced the seizure frequency in the Kcnq2 mutant mice. These observations suggest that reduction of SCN8A may be therapeutic for genetic epilepsies resulting from mutations in these potassium channel genes.


Assuntos
Epilepsia , Canal de Potássio KCNQ2 , Canal de Potássio Kv1.1 , Canal de Sódio Disparado por Voltagem NAV1.6 , Proteínas do Tecido Nervoso , Animais , Epilepsia/genética , Canal de Potássio KCNQ2/genética , Canal de Potássio Kv1.1/genética , Camundongos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Proteínas do Tecido Nervoso/genética , Oligonucleotídeos Antissenso
10.
Neurotherapeutics ; 18(3): 1564-1581, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34386906

RESUMO

Neonatal seizures are a common neurologic emergency for which therapies have not significantly changed in decades. Improvements in diagnosis and pathophysiologic understanding of the distinct features of acute symptomatic seizures and neonatal-onset epilepsies present exceptional opportunities for development of precision therapies with potential to improve outcomes. Herein, we discuss the pathophysiology of neonatal seizures and review the evidence for currently available treatment. We present emerging therapies in clinical and preclinical development for the treatment of acute symptomatic neonatal seizures. Lastly, we discuss the role of precision therapies for genetic neonatal-onset epilepsies and address barriers and goals for developing new therapies for clinical care.


Assuntos
Anticonvulsivantes/uso terapêutico , Eletroencefalografia/métodos , Moduladores GABAérgicos/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Eletroencefalografia/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Humanos , Recém-Nascido , Canais de Potássio/agonistas , Canais de Potássio/fisiologia , Convulsões/diagnóstico
11.
Epilepsia ; 62(5): 1268-1279, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33735460

RESUMO

OBJECTIVES: Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. METHODS: In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. RESULTS: To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. SIGNIFICANCE: Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.


Assuntos
Encéfalo/fisiopatologia , Modelos Animais de Doenças , Epilepsia/fisiopatologia , Malformações do Desenvolvimento Cortical do Grupo I/fisiopatologia , Animais , Humanos , Ratos
12.
Epilepsia ; 61(8): e85-e89, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32614070

RESUMO

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients' epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Trombocitopenia/epidemiologia , Ácido Valproico/uso terapêutico , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
13.
Semin Neurol ; 40(2): 246-256, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143234

RESUMO

Neonates are exquisitely susceptible to seizures due to several physiologic factors and combination of risks that are uniquely associated with gestation, delivery, and the immediate postnatal period. Neonatal seizures can be challenging to identify; therefore, it is imperative that clinicians have a high degree of suspicion for seizures based on the clinical history or the presence of encephalopathy with or without paroxysmal abnormal movements. Acute symptomatic neonatal seizures are due to an acute brain injury, whereas neonatal-onset epilepsy may be related to underlying structural, metabolic, or genetic disorders. Though initial, acute treatment is similar, long-term treatment and prognosis varies greatly based on underlying seizure etiology. Early identification and treatment are likely important for long-term outcomes in acute symptomatic seizures, though additional studies are needed to understand optimal seizure control metrics and the ideal duration of treatment. Advances in genetic medicine are increasingly expanding our understanding of neonatal-onset epilepsies and will continue to open doors for personalized medicine to optimize outcomes in this fragile population.


Assuntos
Doenças do Recém-Nascido , Convulsões , Humanos , Recém-Nascido , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/terapia
14.
Epilepsy Res ; 161: 106289, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32088518

RESUMO

OBJECTIVE: To determine whether clinical outcomes are improved after repeat surgery for medically refractory epilepsy in children. METHODS: This is a single-center retrospective cohort analysis of all patients who received repeat resective surgery for ongoing seizures from 2000-2017. From a total of 251 consecutive individual epilepsy surgical patients for focal resection, 53 patients met study inclusion criteria and had adequate follow-up documented. RESULTS: Median age of seizure-onset was 2.0-years-old (IQR 0.3-5.5 years). The median age at first epilepsy surgery was 6.3-years-old (IQR 2.9-9.2 years) and at second epilepsy surgery was 8.4-years-old (IQR 4.7-12.6 years). Overall, 53 % (n = 28) of this series achieved Engel Class I (seizure freedom); with improved seizure control (Engel Class I-II) in 83 % (n = 44) of the cohort. 64 % (n = 34) had one reoperation; 26 % (n = 14) had two; and 9% (n = 5) had three. Pathology: 58 % (n = 31) had focal cortical dysplasia; 13 % (n = 10) tumor; 9% (n = 5) encephalitis; 6% (n = 3) gliosis; 4% (n = 2) mesial temporal sclerosis; and 2% (n = 1) hemimegalencephaly. Tumor pathology was associated with increased chance (p = 0.01) for seizure freedom (90 % of tumor patients had Engel Class I outcome). MTS had worse outcome with both patients having ongoing seizures (Engel II-IV). There were 6 patients who developed post-operative hemiparesis; one was unplanned but resolved. SIGNIFICANCE: Reoperation for pediatric epilepsy surgery can lead to seizure freedom in many cases and improved seizure control in most cases. Reoperation for brain tumor pathology is associated with a high rate of seizure freedom.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia/cirurgia , Malformações do Desenvolvimento Cortical/cirurgia , Reoperação , Adolescente , Criança , Pré-Escolar , Epilepsia/complicações , Feminino , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/complicações , Neuroimagem/métodos , Procedimentos Neurocirúrgicos , Reoperação/métodos , Convulsões/cirurgia , Resultado do Tratamento
15.
Ann Neurol ; 87(3): 339-346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31943325

RESUMO

OBJECTIVE: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. METHODS: ASO treatment was tested in a conditional mouse model with Cre-dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/- haploinsufficient mouse model of Dravet syndrome was also treated. ASO was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. RESULTS: We observed a dose-dependent increase in length of survival from 15 to 65 days in the Scn8a-R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. INTERPRETATION: Reduction of Scn8a transcript by 25 to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies. Ann Neurol 2020;87:339-346.


Assuntos
Encefalopatias/prevenção & controle , Epilepsias Mioclônicas/prevenção & controle , Canal de Sódio Disparado por Voltagem NAV1.6/efeitos dos fármacos , Animais , Encefalopatias/complicações , Encefalopatias/mortalidade , Relação Dose-Resposta a Droga , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/mortalidade , Feminino , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/administração & dosagem , Oligonucleotídeos Antissenso/farmacologia , Convulsões/complicações , Convulsões/prevenção & controle
16.
Curr Treat Options Neurol ; 20(12): 52, 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30315507

RESUMO

PURPOSE OF REVIEW: Dravet syndrome is a rare but severe genetic epilepsy that has unique treatment challenges. This is a review of current and future potential treatment options. RECENT FINDINGS: Treatment for Dravet syndrome should encompass many aspects of the syndrome such as gait, behavior, and nutrition, as well as focus on seizure control. Many sodium channel blockers should be avoided as they are likely to exacerbate seizures. Current options for treatment include valproic acid, clobazam, stiripentol, and ketogenic diet. Testing is underway for several new treatment options with unique mechanisms of action and therapeutic targets, including the serotonin system and genetic modulation. Accurate and early diagnosis of Dravet syndrome will lead to avoidance of medications that may exacerbate seizures. Additionally, a multi-disciplinary approach and careful planning for management of episodes of status epilepticus may lead to improved outcomes. Ongoing research for novel approaches to treatment creates optimism for future improvement in outcomes.

17.
Sci Rep ; 7(1): 17624, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29247175

RESUMO

Local and controlled delivery of therapeutic agents directly into focally afflicted tissues is the ideal for the treatment of diseases that require direct interventions. However, current options are obtrusive, difficult to implement, and limited in their scope of utilization; the optimal solution requires a method that may be optimized for available therapies and is designed for exact delivery. To address these needs, we propose the Biocage, a customizable implantable local drug delivery platform. The device is a needle-sized porous container capable of encasing therapeutic molecules and matrices of interest to be eluted into the region of interest over time. The Biocage was fabricated using the Nanoscribe Photonic Professional GT 3D laser lithography system, a two-photon polymerization (2PP) 3D printer capable of micron-level precision on a millimeter scale. We demonstrate the build consistency and features of the fabricated device; its ability to release molecules; and a method for its accurate, stable delivery in mouse brain tissue. The Biocage provides a powerful tool for customizable and precise delivery of therapeutic agents into target tissues.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/administração & dosagem , Sefarose/administração & dosagem , Animais , Camundongos , Camundongos Endogâmicos C57BL , Impressão Tridimensional
18.
Neuron ; 96(2): 387-401.e6, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29024662

RESUMO

Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy.


Assuntos
Encéfalo/metabolismo , Proteínas CLOCK/deficiência , Proteínas CLOCK/genética , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Rede Nervosa/metabolismo , Animais , Encéfalo/patologia , Células Cultivadas , Epilepsias Parciais/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/patologia , Estudos Prospectivos
20.
Brain Res ; 1371: 110-20, 2011 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-21111720

RESUMO

Stroke is the major cause of acquired epilepsy in the adult population. The mechanisms of ischemia-induced epileptogenesis are not completely understood, but glutamate is associated with both ischemia-induced injury and epileptogenesis. The objective of this study was to develop an in vitro model of epileptogenesis induced by glutamate injury in organotypic hippocampal slice cultures (OHSCs), as observed in stroke-induced acquired epilepsy. OHSCs were prepared from 1-week-old Sprague-Dawley rat pups. They were exposed to 3.5 mM glutamate for 35 minutes at 21 days in vitro. Field potential recordings and whole-cell current clamp electrophysiology were used to monitor the development of in vitro seizure events up to 19 days after injury. Propidium iodide uptake assays were used to examine acute cell death following injury. Glutamate exposure produced a subset of hippocampal neurons that died acutely and a larger population of injured but surviving neurons. These surviving neurons manifested spontaneous, recurrent epileptiform discharges in neural networks, characterized by paroxysmal depolarizing shifts and high frequency spiking in both field potential and intracellular recordings. This model also exhibited anticonvulsant sensitivity similar to in vivo models. Our study is the first demonstration of a chronic model of acquired epilepsy in OHSCs following a glutamate injury. This in vitro model of glutamate injury-induced epileptogenesis may help develop therapeutic strategies to prevent epileptogenesis after stroke and elucidate some of the mechanisms that underlie stroke-induced epilepsy in a more anatomically intact system.


Assuntos
Epilepsia/fisiopatologia , Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Técnicas de Cultura de Órgãos/métodos , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Sobrevivência Celular , Epilepsia/etiologia , Etossuximida/farmacologia , Hipocampo/fisiopatologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Fenobarbital/farmacologia , Fenitoína/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações
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