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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
Epilepsia ; 49(10): 1795-802, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18494784

RESUMO

PURPOSE: Although great advances have been made in the development of treatments for epilepsy, acquired epilepsy following brain injury still comprises approximately 50% of all the cases of epilepsy. Thus, development of drugs that would prevent or decrease the onset of epilepsy following brain injury represents an important area of research. METHODS: Here, we investigated effects of carisbamate (RWJ 333369) on the development and expression of spontaneous recurrent epileptiform discharges (SREDs) and its neuroprotective potential in cultured hippocampal neurons. This model utilizes 3 h of low Mg(2+) treatment to mimic status epilepticus (SE-like) injury in vitro. Following the injury, networks of neurons manifest synchronized SREDs for their life in culture. Neuronal cultures were treated with carisbamate (200 microM) for 12 h immediately after the SE-like injury. The drug was then removed and neurons were patch clamped 24 h following drug washout. RESULTS: Treatment with carisbamate after neuronal injury prevented the development and expression of epileptiform discharges. In the few neurons that displayed SREDs following carisbamate treatment, there was a significant reduction in SRED frequency and duration. In contrast, phenytoin and phenobarbital, when used in place of carisbamate, did not prevent the development and expression of SREDs. Carisbamate was also effective in preventing neuronal death when administered after SE-like injury. CONCLUSIONS: Carisbamate prevents the development and generation of epileptiform discharges and is neuroprotective when administered following SE-like injury in vitro and may offer a novel treatment to prevent the development of epileptiform discharges following brain injuries.


Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Epilepsia/prevenção & controle , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Células Cultivadas , Epilepsia/fisiopatologia , Magnésio/farmacologia , Técnicas de Patch-Clamp/métodos , Fenobarbital/farmacologia , Ratos , Ratos Sprague-Dawley
8.
Eur J Pharmacol ; 558(1-3): 52-9, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17174949

RESUMO

Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg(2+) hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC(50) of 145+/-4.15 nM and 1.68+/-0.19 microM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB(1) receptor since they were blocked by the cannabinoid CB(1) receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus.


Assuntos
Anticonvulsivantes/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Endocanabinoides , Hipocampo/efeitos dos fármacos , Estado Epiléptico/prevenção & controle , Animais , Ácidos Araquidônicos/farmacologia , Células Cultivadas , Glicerídeos/farmacologia , Magnésio/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia
9.
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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