Aggravation of epilepsy by antiepileptic drugs

Antiepileptic drugs may paradoxically worsen seizure frequency or induce new seizure types in some patients with epilepsy. The mechanisms of seizure aggravation by antiepileptic drugs are mostly unknown and may be related to specific pharmacodynamic properties of these drugs. This article provides a review of the various clinical circumstances of seizure exacerbation and aggravation of epilepsy by antiepileptic drugs as well as a discussion of possible mechanisms underlying the occasional paradoxical effect of these drugs. Antiepileptic drug-induced seizure aggravation can occur virtually with all antiepileptic medications. Drugs that aggravate seizures are more likely to have only one or two mechanisms of action, either enhanced gamma-aminobutyric acid-mediated transmission or blockade of voltage-gated sodium channels. Antiepileptic drug-induced seizure exacerbation should be considered and the accuracy of diagnosis of the seizure type should be questioned whenever there is seizure worsening or the appearance of new seizure types after the introduction of any antiepileptic medication.     

Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study

Women with epilepsy have different needs from men, particularly associated with childbearing. Despite clinical guidelines, the care of women with epilepsy remains suboptimal. The aim of this study was to establish whether women with epilepsy recall being given information on topics relating to childbearing. Design of study and methods included a postal questionnaire study of 795 women with epilepsy and of childbearing age. The respondents were identified through both general practices and hospital clinics as part of the Clinical Standards Advisory Group study into Epilepsy Services. Of those women who considered the questions personally relevant, 38-48% recalled receiving information about contraception, pre-pregnancy planning, folic acid and teratogenicity, with lower overall proportions among adolescent women. The proportions that recalled receiving information about vitamin K, safety in child-care and breast-feeding were lower at 12, 24 and 24%, respectively. While it is recognised that information provided may not be recalled, our results suggest that further measures are required to improve the effectiveness of information provision in the UK in relation to women of childbearing age with epilepsy.     

Cognitive side effects of anti-epileptic drugs. The relevance in childhood epilepsy.

In recent years several new anti-epileptic drugs have been introduced, also for the treatment of childhood epilepsy. A major concern is their effect on learning and cognitive development. Testing the genuine effects on cognition of the anti-epileptic drugs is methodologically not easy. At this moment there are very few controlled trials that systematically examine the cognitive side effects of anti-epileptic drugs in childhood epilepsy. The available data indicate that the newer anti-epileptic drugs have a safe cognitive profile when prescribed correctly at the right dose and in monotherapy. Possible negative effects are mainly found for speed of processing and attention processes. As these processes are important instruments in every day learning and cognition, it is necessary to test these newer anti-epileptic drugs in well designed studies and in specific childhood epilepsy syndromes.     

Aggravation of epilepsy by valproate sodium in a child with cryptogenic localization-related epilepsy

We report a paradoxical effect of valproate sodium (VPA) observed in a 3-year-old girl with cryptogenic localization-related epilepsy. On admission she experienced two types of seizures that were confirmed by ictal EEGs : complex partial seizures (CPSs) originating from the left hemisphere and combined seizures that began with repetitive myoclonic seizures immediately followed by a CPS. These myoclonic seizures did not possess asymmetrical features, but the ictal EEGs showed left-side dominant multiple spike-waves. The patent's interictal EEGs on admission showed left posterior temporal- parietal spikes during wakefulness and frequent diffuse spike-waves during sleep. In the process of introduction and increase in the dosage of VPA, an aggravation of epileptic discharges, especially a dramatic increase in diffuse spike-waves during sleep, was observed. In the same period of time, myoclonic seizures not followed by CPS newly appeared, and there was an increase in the frequency of CPSs and combined seizures. Marked improvement of epileptic discharges, namely the disappearance of diffuse discharges, and complete suppression of all types of seizures were achieved by the introduction of carbamazepine (CBZ) along with the withdrawal of VPA. During the clinical course, the patient did not display any signs or symptoms of VPA encephalitis, overdose of VPA or metabolic aberration. The paradoxical effect of CBZ in localization-related epilepsy is well-known, yet in this case, VPA displayed a similar paradoxical effect. Additionally, CBZ was efficacious in the suppression of secondary bilateral synchrony on EEG and also successfully controlled CPSs, combined seizures and myoclonic seizures.     

关于抗癫(癎)药物治疗靶点的探讨

癫(癎)是一种发病率很高的神经系统疾病,严重影响患者的身心健康,对患者的生活质量有很大影响.目前临床上对癫痫的治疗仍以药物治疗为主.自1912年苯巴比妥被发现,直到1936年出现了苯妥英,1964年丙戊酸钠问世,这几种抗癫(癎)药物(AEDs)至今仍在使用.     

Perioperative substitution of anti-epileptic drugs

A common problem in brain and abdominal surgery is the perioperative substitution of antiepileptic drugs (AEDs) when patients are temporarily unable to take these drugs orally. We searched the literature for clinical trials with patients or healthy volunteers in whom non-oral formulations of AEDs as substitution were tested. Different search engines, handbooks, expert opinion and our own experience, were used. Pharmaceutical companies were approached for recommendations. This led to three categories of replacement: 1. commercial alternative (n = 10) for clonazepam, diazepam, lacosamide, levetiracetam, lorazepam, midazolam, nitrazepam, phenobarbital, phenytoin, and valproic acid; 2. alternatives that must be prepared (n = 6) for carbamazepine, clobazam, lamotrigine, oxcarbazepine, primidone, topiramate; 3. no alternative (n = 7) for ethosuccimide, felbamate, retigabine, stiripentol, tiagabine, vigabatrin, zonisamide. Thus, for a substantial number of AEDs, unofficial perioperative treatment strategies need to be followed for lack of alternatives to oral administration. There is little clinical research addressing the equivalence of oral and parenteral formulas. Perioperative substitution of AEDs is an underestimated problem, and may increase the risk of postoperative seizures.     

正确应用抗癫(癎)药物治疗

癫痫是一种常见的神经系统疾病，目前癫痫的治疗主要是依靠西药治疗，包括传统抗癫痫药物（如卡马西平、丙戊酸等）和新型抗癫痫药物（如托吡酯、奥卡西平等）。如何针对每一例患者选用合理、有效的抗癫痫药物是广大医生和患者最为关注的问题。近年来一些国际权威组织相继发表了癫痫治疗指南，如何正确解读指南并灵活应用于实践，     

Prevalence of epilepsy in Saudi pregnant women and possible effects of anti-epileptic drugs on pregnancy outcomes

Objectives:To determine the prevalence of epilepsy in Saudi pregnant women and estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities. It also aimed to report the teratogenic effects of anti-epileptic drugs as observed in neonates.Methods:This prospective study was conducted at King Fahd University Hospital from June 2018 to July 2019. Sixty-eight pregnant women diagnosed with epilepsy were included in this study. Seizure types and their frequencies were recorded along with anti-epileptic drug therapies and their association with fetal/neonatal malformations.Results:Out of 68 epileptic pregnant females, 30 (44.1%) experienced focal seizures and 38 (55.9%) experienced generalized seizures. Thirty-nine (57.3%) received monotherapy, 21 (30.9%) received polytherapy and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Thirty-six (52.9%) patients experienced no change in seizure frequency during pregnancy, 19 (27.9%) experienced increase in seizure frequency and 13 (19.1%) showed decreased seizure frequency. The pregnancy outcomes analysis showed 2 (2.9%) intrauterine fetal deaths, whereas 4 (4.9%) neonates showed facial and/or organ malformations.Conclusion:The frequency of seizures was found to increase in only 27.9% of the pregnant women in the sample. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that for the patient group using monotherapy, the rate of healthy babies was higher than that of the group using polytherapy.

Epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures, with cognitive, neurobiological, psychological, and social consequences.1 An epileptic seizure is “a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain”.1 According to the World Health Organization (WHO), it is the second most burdensome neurological disorder that can cause cognitive, neurobiological and psychosocial abnormalities in the suffering individuals.2,3 In women with epilepsy (WWE), disruption of menstruation cycle, fertility, pregnancy, fetus development, menopause and sexual dysfunction has been reported.4 The condition becomes more critical when WWE become pregnant. It has been estimated that the maternal death rate for this group is 10 times higher as compared to normal pregnancy cases.5 Moreover, the frequent seizures during pregnancy have been known to jeopardize the cognitive and physical development of the fetus.6 Thus, epilepsy is not only harmful for the mother but may also pose potentially worse consequences for the fetus.The management of seizures through anti-epileptic drugs (AEDs) in pregnant WWE is a challenging task because during the risk-benefit assessment, the needs of the suffering WWE against the potential adverse effects of AEDs on the fetus need to be taken into account as well.7 Several studies suggest the association of AEDs with congenital malformations which put physicians in a difficult spot. In this challenging situation, the attending physician is expected to choose between the available treatment options (mono- or polytherapy) during pregnancy. Therefore, the most critical issue is the regulation of the minimum effective dose of AEDs during pregnancy to prevent any damage to the fetus from seizures as well as AEDs.8A plethora of evidence has reported the prevalence of epilepsy and its possible outcomes in the general population.2,9,10 However, less is known about the prevalence of epilepsy in Saudi pregnant women, the association of AEDs with the frequency of seizures and their impact on fetal development. The quantification of epileptic pregnant patients and their pregnancy outcomes is important in order to provide optimal counseling and patient care. Therefore, the aims of this study were multifold: (1) to determine the prevalence of epilepsy in pregnant females, (2) to estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities, (3) to assess pregnancy outcomes and possible birth defects in WWE taking monotherapy, polytherapy or no therapy during pregnancy.     

Saccadic eye movements and anti-epileptic drugs

Saccadic eye movements can be used to evaluate different aspects of brain function, and in this article we are concerned with possible applications in relation to anti-epileptic drug treatment. Recent improvements in the technology of measurement have improved the sensitivity and objectivity of the measures. Here we review the neurophysiology of saccades, their classification, their anatomical basis and cortical control, and then published research articles concerned with the influence of anti-epileptic drugs on saccades and their parameters. It seems likely that certain anti-epileptic drugs (especially those acting on ion channels) exert their effect on saccades through ion channels, and this may have relevance to clinical and pharmacogenetic studies.     

Comparison the cognitive effect of anti-epileptic drugs in seizure-free children with epilepsy before and after drug withdrawal

We studied the cognitive effects of antiepileptic drugs (AED), by investigating epileptic children who were seizure-free for at least 2 years and who had undergone fixed monotherapy. Seventy consecutive epileptic children (25 with carbamazepine (CBZ), 22 with phenobarbital (PB), and 23 with valproate (VPA)) were examined by Wechsler Intelligence Scale for Children-Revised (WISC-R) and auditory event-related potentials (P(300)) at three sessions: before AED reduction, then 1 and 7 months after complete withdrawal of treatment. There were no significant differences in IQ and subtests scores of WISC-R in any group at any of the three sessions. P(300) latencies were significantly increased in the children receiving PB but not in children receiving CBZ or VPA. P(300) amplitudes were increased but not significantly different among the three groups. These findings suggest that PB may affect cognitive function on children, but the changes of P(300) latencies may improve after discontinuation.     

抗癫(癎)药物的临床实践:热点与思考

2001年国际抗癫痫联盟专门组建的3个委员会在对过去的20年中癫痫病学所取得的科学进步进行总结后认为，既要保持以前有关癫痫知识的框架，又要反映最近20年癫痫病学取得的科学进展是不可能的，主张重建癫痫的知识框架，此举受到赞同。随后，国际抗癫痫联盟发表了新的癫痫词汇库，统一了国际上有关癫痫的描述，并在阿根廷国际癫痫大会上通过了新的癫痫分类和新的癫痫诊断方案。2005年，国际抗癫痫联盟又提出了新的癫痫定义。最近几年，国际抗癫痫联盟有关癫痫的新概念逐渐集中到癫痫病学最为核心的治疗学部分，在发表有关癫痫治疗指南以后，     

Inhibition of quisqualate-induced seizures by glutamic acid diethyl ester and anti-epileptic drugs

Summary Glutamic acid diethyl ester (GDEE) is a glutamate antagonist which acts preferentially at the quisqualate-sensitive receptor and has been shown to be an effective anticonvulsant in alcohol withdrawal and homocysteine-induced seizures but ineffective in other seizure models. To better characterize the role of the quisqualate-sensitive receptor in the generation of seizures, quisqualate was administered to mice by intracerebroventricular (ICV) route and immediate onset generalized seizures were observed. The anticonvulsant properties of GDEE and commonly used antiepileptic drugs (AEDs) were investigated with this seizure model. GDEE given by intraperitoneal blocked quisqualate-induced seizures dose-dependently. Diphenylhydantoin (50 mg/kg IP), carbamazepine (50 mg/kg IP), diazepam (1; 4 mg/ kg IP), phenobarbital (40; 80 mg/kg IP), and valproic acid (250; 340 mg/kg IP) were also administered prior to quisqualate-seizure induction. Only valproic acid blocked seizures at nonsedating doses. The GABA transaminase inhibitor aminooxyacetic acid (20 mg/kg IP) was ineffective, suggesting that here valproic acid is active at excitatory receptors rather than by potentiating GABA post-synaptic inhibition. These data are consistent with the hypothesis that the quisqualate-sensitive receptor is involved in some forms of clinically observed seizures, particularly those which are controlled by valproic acid.     

A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs.

OBJECTIVES: Side-effects of anti-epileptic drugs (AEDs) may be overlooked in patients with epilepsy in everyday clinical practice. The aim of this study was to assess the prevalence and severity of subjective complaints in patients who were considered to be well-controlled and to assess whether these complaints are related to medication, personality traits, or other determinants. METHODS: We included patients with epilepsy who were considered to be well-controlled in a cross-sectional study in seven hospitals in the Netherlands. Their medication had not been changed for six months and an apparent reason to change the medication was lacking at the time of enrolment. Subjective complaints were assessed with a 46-item questionnaire. Using multivariable linear regression modeling, we assessed whether patient characteristics, epilepsy characteristics, medication, quality of life (Qolie-10), and personality traits (SCL-90) explained the presence and severity of complaints. RESULTS: Of 173 included patients, 67% reported moderate to severe subjective complaints on the questionnaire. Cognitive complaints were reported most frequently. Multivariate modeling showed that 61% of the variance in reported complaints could be explained by included determinants. The prevalence and severity of complaints was associated with AED polytherapy and higher scores on psycho neuroticism. CONCLUSIONS: Patients who were considered to be well-controlled proved to report an unexpectedly high number of subjective complaints. Both medication and aspects of personality contributed to the level of complaints. Our study illustrates that subjective side-effects are easily overlooked in everyday clinical practice, possibly because in practice a generally phrased question is used to detect side-effects.     

Reporting and analysis of open-label extension studies of anti-epileptic drugs

PURPOSE: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders. METHODS: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis. RESULTS: The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT. CONCLUSIONS: FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.