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1.
Postgrad Med ; 131(7): 479-485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31513436

RESUMO

Objectives: To evaluate clinical, electrophysiological, and neuroradiological factors which correlate with the prognosis in patients with mesial temporal lobe epilepsy (MTLE). Methods: This was a single-center prospective outcome study in patients with MTLE. The patients' family history, clinical characteristics, neurophysiological data (electroencephalography - EEG), neuroimaging, antiepileptic therapy, and outcome were collected and analyzed. The population was divided into four groups depending on the frequency of the seizures when they attended their last follow up. All variables and outcome measures were compared between the four groups. Results: In total 83 consecutive patients were included within the four groups. Group 1 (seizure-free) consisted of 7 patients, (9%), Group 2 (rare seizures) consisted of 15 patients (18%), Group 3 (often seizures) consisted of 30 patients (36%), and Group 4 (very often seizures) consisted of 31 patients (37%). The groups did not differ significantly in demographic characteristics. There was a strong positive correlation between resistance to therapy and sleep activation on EEG (p = 0.005), occurrence of focal to bilateral seizures (p = 0.007), automatisms (p = 0.004), and the number of previously used antiepileptic drugs (AEDs) (p = 0.002). There was no association between febrile convulsions (FC), hippocampal sclerosis (HS), and the outcome that was found. Conclusion: MTLE is a heterogeneous syndrome. Establishing the factors responsible for, and associated with, drug resistance is important for optimal management and treatment, as early identification of drug resistance should then ensure a timely referral for surgical treatment is made. This prospective study shows that sleep activation on EEG, ictal automatisms, occurrence of focal to bilateral tonic-clonic seizures, and increased number of tried AEDs are negative prognostic factors.


Assuntos
Automatismo/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Hipocampo/patologia , Convulsões Febris/fisiopatologia , Sono/fisiologia , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Esclerose , Adulto Jovem
2.
Cochrane Database Syst Rev ; 8: CD008295, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425617

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Felbamato/uso terapêutico , Humanos , Fenilcarbamatos/efeitos adversos , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/efeitos adversos , Propilenoglicóis/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Int J Mol Sci ; 20(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366017

RESUMO

Epilepsy refers to a common chronic neurological disorder that affects all age groups. Unfortunately, antiepileptic drugs are ineffective in about one-third of patients. The complex interindividual variability influences the response to drug treatment rendering the therapeutic failure one of the most relevant problems in clinical practice also for increased hospitalizations and healthcare costs. Recent advances in the genetics and neurobiology of epilepsies are laying the groundwork for a new personalized medicine, focused on the reversal or avoidance of the pathophysiological effects of specific gene mutations. This could lead to a significant improvement in the efficacy and safety of treatments for epilepsy, targeting the biological mechanisms responsible for epilepsy in each individual. In this review article, we focus on the mechanism of the epilepsy pharmacoresistance and highlight the use of a systems biology approach for personalized medicine in refractory epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Genômica/métodos , Medicina de Precisão/métodos , Biologia de Sistemas/métodos , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/genética , Humanos , Variantes Farmacogenômicos
4.
Cochrane Database Syst Rev ; 7: CD005612, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31287157

RESUMO

BACKGROUND: Epilepsy is a common neurological disease that affects approximately 1% of the UK population. Approximately one-third of these people continue to have seizures despite drug treatment. Pregabalin is one of the newer antiepileptic drugs which have been developed to improve outcomes.This is an updated version of the Cochrane Review published in Issue 3, 2014, and includes three new studies. OBJECTIVES: To assess the efficacy and tolerability of pregabalin when used as an add-on treatment for drug-resistant focal epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), on 5 July 2018, MEDLINE (Ovid, 1946 to 5 July 2018), ClinicalTrials.gov (5 July 2018), and the World Health Organization International Clinical Trials Registry Platform (ICTRP, 5 July 2018), and contacted Pfizer Ltd, manufacturer of pregabalin, to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug as an add-on for people of any age with drug-resistant focal epilepsy. Double-blind and single-blind trials were eligible for inclusion. The primary outcome was 50% or greater reduction in seizure frequency; secondary outcomes were seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse effects, and proportion of individuals experiencing adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and assessed trials for eligibility and extracted data. Analyses were by intention-to-treat. We presented results as risk ratios (RR) and odds ratios (OR) with 95% confidence intervals (CIs). Two review authors assessed the included studies for risk of bias using the Cochrane 'Risk of bias' tool. MAIN RESULTS: We included nine industry-sponsored randomised controlled trials (3327 participants) in the review. Seven trials compared pregabalin to placebo. For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 2.28, 95% CI 1.52 to 3.42, 7 trials, 2193 participants, low-certainty evidence). The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 1.99, 95% CI 1.74 to 2.28), indicating a dose-response relationship. Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate-certainty evidence). Participants were significantly more likely to withdraw from pregabalin treatment than placebo for any reason (RR 1.35, 95% CI 1.11 to 1.65, 7 trials, 2193 participants, moderate-certainty evidence) and for adverse effects (RR 2.65, 95% CI 1.88 to 3.74, 7 trials, 2193 participants, moderate-certainty evidence).Three trials compared pregabalin to three active-control drugs: lamotrigine, levetiracetam, and gabapentin. Participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency than those allocated to lamotrigine (RR 1.47, 95% CI 1.03 to 2.12, 1 trial, 293 participants) but not those allocated to levetiracetam (RR 0.94, 95% CI 0.80 to 1.11, 1 trial, 509 participants) or gabapentin (RR 0.96, 95% CI 0.82 to 1.12, 1 trial, 484 participants). We found no significant differences between pregabalin and lamotrigine (RR 1.39, 95% CI 0.40 to 4.83) for seizure freedom, however, significantly fewer participants achieved seizure freedom with add-on pregabalin compared to levetiracetam (RR 0.50, 95% CI 0.30 to 0.85). No data were reported for this outcome for pregabalin versus gabapentin. We found no significant differences between pregabalin and lamotrigine (RR 1.07, 95% CI 0.75 to 1.52), levetiracetam (RR 1.03, 95% CI 0.71 to 1.49), or gabapentin (RR 0.78, 95% CI 0.57 to 1.07) for treatment withdrawal due to any reason or due to adverse effects (pregabalin versus lamotrigine: RR 0.89, 95% CI 0.53 to 1.48; versus levetiracetam: RR 1.29, 95% CI 0.66 to 2.54; versus gabapentin: RR 1.07, 95% CI 0.54 to 2.11). Ataxia, dizziness, somnolence, weight gain, and fatigue were significantly associated with pregabalin.We rated the overall risk of bias in the included studies as low or unclear due to the possibility of publication bias and lack of methodological details provided. We rated the certainty of the evidence as very low to moderate using the GRADE approach. AUTHORS' CONCLUSIONS: Pregabalin, when used as an add-on drug for treatment-resistant focal epilepsy, is significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom. Results demonstrated efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses, however issues with tolerability were noted at higher doses. The trials included in this review were of short duration, and longer-term trials are needed to inform clinical decision making.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Parciais/tratamento farmacológico , Pregabalina/uso terapêutico , Quimioterapia Combinada , Gabapentina , Humanos , Lamotrigina , Levetiracetam , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológico
6.
Paediatr Drugs ; 21(4): 283-290, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179531

RESUMO

BACKGROUND: A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy. OBJECTIVE: The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children's Hospital in Rome, Italy. METHODS: This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98-99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2-5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects. RESULTS: Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required. CONCLUSIONS: These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Adolescente , Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
7.
BMC Neurol ; 19(1): 114, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164100

RESUMO

BACKGROUND: Epigenetics underlying refractory epilepsy is poorly understood. DNA methylation may affect gene expression in epilepsy patients without affecting DNA sequences. Herein, we investigated the association between Carbamazepine-resistant (CBZ-resistant) epilepsy and EPHX1 methylation in a northern Han Chinese population, and conducted an analysis of clinical risk factors for CBZ-resistant epilepsy. METHODS: Seventy-five northern Han Chinese patients participated in this research. 25 cases were CBZ-resistant epilepsy, 25 cases were CBZ-sensitive epilepsy and the remaining 25 cases were controls. Using a CpG searcher was to make a prediction of CpG islands; bisulfite sequencing PCR (BSP) was applied to test the methylation of EPHX1. We then did statistical analysis between clinical parameters and EPHX1 methylation. RESULTS: There was no difference between CBZ-resistant patients, CBZ-sensitive patients and healthy controls in matched age and gender. However, a significant difference of methylation levels located in NC_000001.11 (225,806,929.....225807108) of the EPHX1 promoter was found in CBZ-resistant patients, which was much higher than CBZ-sensitive and controls. Additionally, there was a significant positive correlation between seizure frequency, disease course and EPHX1 methylation in CBZ-resistant group. CONCLUSION: Methylation levels in EPHX1 promoter associated with CBZ-resistant epilepsy significantly. EPHX1 methylation may be the potential marker for CBZ resistance prior to the CBZ therapy and potential target for treatments.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Resistência a Medicamentos/genética , Epilepsia Resistente a Medicamentos/genética , Epóxido Hidrolases/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Metilação de DNA , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Adulto Jovem
8.
J Clin Neurophysiol ; 36(5): 371-374, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31107715

RESUMO

PURPOSE: Magnetoencephalography (MEG) is a noninvasive tool used clinically for presurgical evaluation of patients with medically intractable epilepsy. These recordings require patients to lie still for prolonged periods of time in a magnetically shielded room. Children or uncooperative adults with epilepsy may require sedation to reduce movement artefact and obtain high-quality recordings. Potential challenges related to the use of total intravenous anesthesia in the MEG environment include limited access to the patient's airway, remote location, suppression of cortical activity, and increased patient care expenses. We report our experience with intranasal dexmedetomidine as sedation for intractable epilepsy patients undergoing MEG. METHODS: Sleep deprivation occurred the night before MEG testing. Intranasal dexmedetomidine (2 µg/kg) was administered and oxygen saturation, blood pressure, and pulse rate were recorded continuously on a monitor outside the magnetically shielded room. A recording of spontaneous neuromagnetic activity was immediately followed by median nerve electrical stimulation. RESULTS: Twenty-six patients (mean age 12.2 ± 4.2 years) with medically intractable epilepsy were recorded using this protocol. There were no failures of sedation, and although patients experienced transient bradycardia, none required intervention and the recording did not need to be stopped. In all cases, artefact-free MEG recordings were obtained with sufficient interictal discharges available for source analysis. CONCLUSIONS: Our experience suggests that intranasal dexmedetomidine is an advantageous sedation option for children and adults with intractable epilepsy who are undergoing MEG. Further research is needed to determine the best ways to apply these methods to younger children and those with developmental disabilities.


Assuntos
Dexmedetomidina/administração & dosagem , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Hipnóticos e Sedativos/administração & dosagem , Magnetoencefalografia/métodos , Administração Intranasal , Adolescente , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Criança , Epilepsia Resistente a Medicamentos/fisiopatologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Estudos Retrospectivos
9.
Environ Health Prev Med ; 24(1): 31, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084599

RESUMO

In Japan, because the most common site of drowning among patients with epilepsy is the bathtub, showering is generally recommended as an alternative to bathing. We herein report a case involving a female patient with epilepsy who drowned while showering. She had been diagnosed with epilepsy approximately 25 years previously, and her condition had progressed to refractory epilepsy. Carbamazepine, levetiracetam, lamotrigine, clobazam, and perampanel were prescribed daily. One day while showering, the patient was found lying with her face immersed in water that had accumulated on the floor of the bathtub. A forensic autopsy revealed water in the stomach, trachea, and proximal regions of both lung bronchi as well as white and red foam on the pharynx and larynx. A total of 1.9 µg/mL of lamotrigine, 0.14 µg/mL of carbamazepine, and 0.069 µg/mL of perampanel were detected in the patient's blood. The patient's cause of death was determined to be drowning due to an epileptic seizure. Although the patient was prescribed five types of antiepileptic medication, only three were detected in her blood. The current case demonstrates that drowning can occur while showering, suggesting that it is unsafe for patients with medication nonadherence. To prevent unintentional deaths in the bathroom, we recommend that patients with epilepsy maintain high adherence to all prescriptions and are supervised by a family member, even when showering. The current case is the first autopsy report of a patient with epilepsy who drowned while showering.


Assuntos
Afogamento/etiologia , Afogamento/patologia , Epilepsia Resistente a Medicamentos/patologia , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Autopsia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Japão , Adesão à Medicação
10.
J Clin Neurosci ; 64: 21-22, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954356

RESUMO

This case report details a novel approach to the management of super-refractory status epilepticus (SRSE) in a boy with new-onset seizures progressing to SRSE. After exhausting multiple medications, dexmedetomidine, an α2-adrenoreceptor agonist used for sedation, stopped his SRSE. Dexmedetomidine provides a unique mechanism of action to treat this condition. Further studies are needed to determine its role in SRSE.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dexmedetomidina/uso terapêutico , Malformações do Desenvolvimento Cortical/complicações , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/etiologia , Pré-Escolar , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/etiologia , Humanos , Masculino
11.
Expert Opin Drug Metab Toxicol ; 15(5): 407-415, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30991855

RESUMO

INTRODUCTION: About 40% of patients with epilepsy are associated with drug-resistant seizures, therefore there has been a continuous search for novel treatment approaches. In experimental studies, natural and synthetic cannabimimetic compounds alone or combined with antiepileptic drugs (AEDs) have been extensively studied and cannabidiol, a naturally occurring compound, has been involved in a number of clinical trials. Areas covered: The authors have performed a literature search (PubMed database up to December 2018) for studies evaluating interactions between AEDs and cannabinoid receptor ligands in experimental models of seizures. Clinical data relate to the add-on treatment with cannabidiol. Expert opinion: WIN55,212-2 mesylate (WIN, a non-selective agonist of CB1 and CB2 receptors) significantly potentiated the anticonvulsant activity of various  AEDs in mice. Profound neurotoxic effects accompanied combinations of WIN with conventional AEDs. Among conventional and newer AEDs, ACEA (a selective CB1 receptor agonist) enhanced the protective action of phenobarbital and levetiracetam without accompanying adverse effects or pharmacokinetic interactions. Cannabidiol proved effective in clinical trials, reducing seizure frequency and the most frequently observed adverse effects were diarrhea, somnolence, and poor appetite. The retention rate was within 14-24% (12-14 weeks - 1 year) but it reached the level of 35% after 2 years.


Assuntos
Anticonvulsivantes/administração & dosagem , Canabinoides/administração & dosagem , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Canabinoides/efeitos adversos , Canabinoides/farmacologia , Modelos Animais de Doenças , Interações de Medicamentos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Humanos , Camundongos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacologia
12.
Lancet ; 393(10186): 2135-2145, 2019 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-31005386

RESUMO

BACKGROUND: Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. METHODS: ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. FINDINGS: Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference -9·2% [95% CI -21·9 to 3·5]; p=0·16). One participant in the phenytoin group died at 27 days because of haemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. INTERPRETATION: Levetiracetam is not superior to phenytoin for second-line management of paediatric convulsive status epilepticus. FUNDING: Health Research Council of New Zealand, A+ Trust, Emergency Medicine Foundation, Townsville Hospital Private Practice Fund, Eric Ormond Baker Charitable Fund, and Princess Margaret Hospital Foundation.


Assuntos
Anticonvulsivantes/administração & dosagem , Levetiracetam/administração & dosagem , Fenitoína/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Adolescente , Idoso , Anticonvulsivantes/efeitos adversos , Austrália , Criança , Pré-Escolar , Esquema de Medicação , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Serviço Hospitalar de Emergência , Feminino , Humanos , Lactente , Levetiracetam/efeitos adversos , Masculino , Nova Zelândia , Fenitoína/efeitos adversos , Resultado do Tratamento
13.
Lancet ; 393(10186): 2125-2134, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31005385

RESUMO

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. METHODS: This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91-1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. FUNDING: National Institute for Health Research Health Technology Assessment programme.


Assuntos
Anticonvulsivantes/administração & dosagem , Levetiracetam/administração & dosagem , Fenitoína/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Esquema de Medicação , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Serviço Hospitalar de Emergência , Feminino , Humanos , Lactente , Levetiracetam/efeitos adversos , Masculino , Fenitoína/efeitos adversos , Resultado do Tratamento , Reino Unido
15.
Seizure ; 67: 40-44, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30875668

RESUMO

PURPOSE: To systematically evaluate the duration of focal onset seizures under medication withdrawal as a function of drug half-life. METHODS: Adults with drug resistant focal epilepsy and invasive electroencephalographic (iEEG) recording between 01/2006 and 06/2016 (n = 128) were identified. Patients with multifocal or unknown epileptic foci were excluded, as well as subclinical seizures, isolated auras, or status epileptic. Antiepileptic drugs (AEDs) were withdrawn upon admission. The seizure duration was determined based on the invasive EEG data, and the latency since start of the monitoring was noted in hours. A negative binomial mixed model was used to compare the seizure durations before and after a cut-off, which was set at 2.5 half-lives of the individual anticonvulsive medication as this is thought to separate therapeutic and ineffective drug levels. RESULTS: In total, 70 patients were included in the study and the duration of 672 seizures analyzed. On average, the patients were treated with 2.36 ± 0.78 AEDs. The individual cut-off of 2.5 half-lives was on average reached after 95.02 ± 80.18 h. The seizure frequency (321 vs. 351) and the rate of generalization (15.6% vs. 16.8%) was comparable before and after the individual cut-off point. The mean seizure duration was not statistically significantly prolonged after 2.5 half-lives by a factor of 1.168 for focal onset seizures (p = 0.090) and a factor of 1.091 for secondary generalized seizures (p = 0.545). CONCLUSIONS: Although AED withdrawal increases the likelihood for epileptic seizures, it did not prolong the seizure duration, nor did it increase the rate of secondary generalization in our study.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Convulsões/fisiopatologia , Adulto , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Eletrocorticografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Convulsões/tratamento farmacológico
16.
Cochrane Database Syst Rev ; 3: CD011501, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30920649

RESUMO

BACKGROUND: Epilepsy is one of the most common neurological disorders. It is estimated that up to 30% of patients with epilepsy continue to have epileptic seizures despite treatment with an antiepileptic drug. These patients are classified as drug-resistant and require treatment with a combination of multiple antiepileptic drugs. Brivaracetam is a third-generation antiepileptic drug that is a high-affinity ligand for synaptic vesicle protein 2A. This review investigates the use of brivaracetam as add-on therapy for epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of brivaracetam when used as add-on treatment for people with drug-resistant epilepsy. SEARCH METHODS: We searched the following databases on 9 October 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); Medline (Ovid) 1946 to 8 October 2018; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Originally we also searched SCOPUS as a substitute for Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL. SELECTION CRITERIA: We sought randomised controlled trials with parallel-group design, recruiting people of any age with drug-resistant epilepsy. We accepted studies with any level of blinding (double-blind, single-blind, or unblind). DATA COLLECTION AND ANALYSIS: In accordance with standard methodological procedures expected by the Cochrane Collaboration, two review authors independently assessed trials for inclusion before evaluating trial quality and extracting relevant data. The primary outcome to be assessed was 50% or greater reduction in seizure frequency. Secondary outcomes were: seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse events, the proportion of participants who experienced any adverse events, and drug interactions. We used an intention-to-treat (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: The review included six trials representing 2411 participants. Only one study included participants with both focal and generalised onset seizures; the other five trials included participants with focal onset seizures only. All six studies included adult participants between 16 and 80 years old, and treatment periods ranged from 7 to 16 weeks. We judged two studies to have low risk of bias and four to have unclear risk of bias. One study failed to provide details on the method used for allocation concealment, and one did not report all outcomes prespecified in the trial protocol. One study did not describe how blinding was maintained, and another noted discrepancies in reporting.Participants receiving brivaracetam add-on were significantly more likely to experience a 50% or greater reduction in seizure frequency than those receiving placebo (RR 1.81, 95% CI 1.53 to 2.14; 6 studies; moderate-quality evidence). Participants receiving brivaracetam were also significantly more likely to attain seizure freedom (RR 5.89, 95% CI 2.30 to 15.13; 6 studies; moderate-quality evidence). The incidence of treatment withdrawal for any reason (RR 1.27, 95% CI 0.94 to 1.74; 6 studies; low-quality evidence), as well as the risk of participants experiencing one or more adverse events (RR 1.08, 95% CI 1.00 to 1.17; 5 studies; moderate-quality evidence), was not significantly different following treatment with brivaracetam compared to placebo. However, participants receiving brivaracetam did appear to be significantly more likely to withdraw from treatment specifically because of adverse events compared with those receiving placebo (RR 1.54, 95% CI 1.02 to 2.33; 6 studies; low-quality evidence). AUTHORS' CONCLUSIONS: Brivaracetam, when used as add-on therapy for patients with drug-resistant epilepsy, is effective in reducing seizure frequency and can aid patients in achieving seizure freedom. However, add-on brivaracetam is associated with a greater proportion of treatment withdrawals due to adverse events compared with placebo. It is important to note that only one of the eligible studies included participants with generalised epilepsy. None of the studies included participants under the age of 16, and all studies were of short duration. Consequently, these findings are mainly applicable to adult patients with drug-resistant focal epilepsy. Future research should thus focus on investigating the tolerability and efficacy of brivaracetam during longer-term follow-up, and should also assess the efficacy and tolerability of add-on brivaracetam in managing other types of seizures and its use in other age groups.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Anticonvulsivantes/efeitos adversos , Interações de Medicamentos , Quimioterapia Combinada , Humanos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Pirrolidinonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Seizure ; 67: 65-70, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30909164

RESUMO

PURPOSE: Suicidality including suicidal ideation and attempt has been a critical issue in people with epilepsy, especially in people with drug-resistant epilepsy (PWDRE). Clinicians commonly ask about adverse effects of antiepileptic drugs (AEDs) using something like the Liverpool Adverse Events Profile (LAEP) at epilepsy clinics, but suicide is usually not of interest. A high risk of suicidality can increase mortality by committing suicide in PWDRE. This study aimed to investigate whether clinicians can discern a high risk of suicidality in PWDRE by referring to the LAEP. METHODS: We recruited PWDRE, aged from 19 to 68. They completed the 21-item LAEP, the suicidality module of the Mini International Neuropsychiatric Interview, and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Through receiver operating characteristic curve analysis, we tested the usefulness of LAEP to detect a high risk of suicide. By this, we determined each cutoff point of the total LAEP score and the number of severe LAEP items, for detecting the risk. RESULTS: A hundred forty-four PWDRE participated in this study. Among them, 36 PWDRE (25.0%) had a high risk of suicidality. Either >45 of the total LAEP score or >8 of the number of severe LAEP items was a suggested optimal cutoff point for discerning the high risk of suicidality. LAEP had a correlation with the suicidality item of the NDDI-E. CONCLUSION: The LAEP may inform a high risk of suicidality in PWDRE. Referring to this, clinicians can discern suicidal problems in their epilepsy clinics.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia Resistente a Medicamentos/diagnóstico , Suicídio , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Escalas de Graduação Psiquiátrica , Curva ROC , Medição de Risco , Adulto Jovem
19.
Acta Neurol Belg ; 119(3): 423-430, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30840220

RESUMO

The objective of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in residential patients at our epilepsy centre. We assessed retrospectively 80 patients (mean age 36.2 years, range 18-63 years; 29 female) with intellectual disability (ID) and drug-resistant epilepsy using an industry-independent, non-interventional study design based on standardised seizure records. Evaluation, including calculation of retention rate, was carried out for the intervals 3-6, 9-12 and 21-24 months after LCM initiation. The Clinical Global Impression scale (CGI) was used to allow assessment of qualitative changes in seizure severity and clinical status. CGI improved for 61% of the patients. The responder rate was 48%; ten patients (13%) became seizure free. The response was not related to the degree of ID. The retention rates after 12 and 24 months were 71% and 65%, and were significantly lower in patients taking other sodium-channel blockers (SCBs; 76% vs. 55%). The occurrence of adverse events (AEs) was related to the administration of concomitant SCBs (48% with SCBs vs. 26% without). Sedation (15%), ataxia (13%), vertigo (11%), and nausea (9%) were the commonest AEs. While 60% of our patients had concomitant psychiatric diagnosis, we found no relevant effect of this on challenging behaviour. Adjunctive LCM may provide an antiepileptic treatment option for patients with ID with or without additional psychiatric diagnosis. The occurrence of AEs and the LCM retention rate were affected by concomitant SCB use but not by psychiatric comorbidity.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Deficiência Intelectual , Lacosamida/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Comorbidade , Epilepsia Resistente a Medicamentos/epidemiologia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Deficiência Intelectual/epidemiologia , Lacosamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos , Adulto Jovem
20.
Medicine (Baltimore) ; 98(8): e14698, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813219

RESUMO

RATIONALE: The phenotypic spectrum caused by SCN2A mutations includes benign neonatal/infantile seizures, Ohtahara syndrome, infantile spasms, West syndrome, and other unclassified epileptic phenotypes. Mutations in SCN2A have been implicated in neonatal seizure cases. Here, we described a Chinese family with 2 members having juvenile-onset myoclonus and identified a novel SCN2A point mutation within this family. PATIENT CONCERNS: The 21-year-old male proband suffered from frequent myoclonus at 11 years old with subsequent progressive ataxia. His elder maternal half-sister also experienced myoclonus. Genomic DNA of the patients was extracted from the peripheral blood cells of the proband, elder maternal half-sister, parents, and uncle of the proband. Targeted next-generation sequencing was used to screen gene mutations in the proband. The potential functional effects of mutations within SCN2A were predicted In silico analyses. DIAGNOSES: Genetic testing revealed a novel SCN2A variant, c.T4820C, which contains a highly conserved amino acid substitution within segment S5 (p.V1607A). This mutation was predicted to produce a dysfunctional Nav1.2 protein by Mutation Taster and Protein Variation Effect Analyzer (PROVEAN). Genotype-phenotype correlation showed an incomplete penetrance of p.V1607A. INTERVENTIONS: The proband was treated by multiple antiepileptic drugs. These included carbamazepine, oxcarbazepine, valproate, and topiramate. OUTCOMES: The duration of follow up was 2 years, and the proband developed drug-resistant epilepsy. LESSONS: The case gives us the lesson that SCN2A mutation can contribute to juvenile-onset myoclonus. Our findings extend the spectrums of SCN2A mutations and the clinical features of patients with SCN2A mutations.


Assuntos
Carbamazepina , Epilepsia Mioclônica Juvenil , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Ataxia/diagnóstico , Ataxia/etiologia , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Progressão da Doença , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genética , Eletroencefalografia/métodos , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Anamnese , Mutação , Epilepsia Mioclônica Juvenil/diagnóstico , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Epilepsia Mioclônica Juvenil/genética , Exame Neurológico/métodos , Oxcarbazepina/administração & dosagem , Oxcarbazepina/efeitos adversos , Linhagem , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversos
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