Which drug for the adult epileptic patient: phenytoin or valproate?

A series of 140 previously untreated patients with tonic-clonic or partial seizures were randomised to receive either phenytoin or sodium valproate. There was no difference between the treatment groups in pretreatment variables that might influence outcome. Sodium valproate and phenytoin in the treatment of tonic-clonic or partial seizures showed no difference in efficacy as regards time to two year remission or time to first seizure. When the possible prognostic factors were studied, including history and results of clinical examination and investigations before treatment; the only factor which influenced the proportion of patients achieving two year remission was type of seizure. Patients with a clinical history of partial seizures did significantly less well than those with a history of tonic-clonic seizures only. This study showed no major difference in efficacy between sodium valproate and phenytoin in adults with recent onset of epilepsy, irrespective of the type of seizures that the patient suffered.     

Solitary epileptic seizure--the risk of recurrence

Patients experiencing solitary unprovoked epileptic seizure have different risks of recurrence. The possible risk factors include in particular: structural cerebral lesion and its cause, history of febrile seizures, family history of epilepsy, the type of seizure, epileptiform EEG discharges and the problem of initiation or (or not initiation) of antiepileptic treatment after the first paroxysm. The factors shown above were evaluated in a group of 30 patients with solitary unprovoked epileptic seizure. Regarding recurrence of epileptic seizure, the only significant factor appeared to be initiation of treatment after the first unprovoked paroxysm (p<0.001). We observed a 30% and 33.33% risk of recurrence following the initial epileptic seizure in patients after the first unprovoked seizure in less than 1 and 3 years, respectively.     

Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

New antiepileptic drugs: a systematic review of their efficacy and tolerability.

OBJECTIVES: To evaluate the efficacy and tolerability of the newly developed antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide in patients with refractory partial epilepsy. DESIGN: Systematic review of published and unpublished randomised controlled trials of add-on treatment with new antiepileptic drugs. SUBJECTS: 20 published and eight unpublished trials representing 3883 patients with refractory partial epilepsy. MAIN OUTCOME MEASURES: Proportion of patients who (a) showed 50% or greater reduction in frequency of seizures (50% responders) and (b) withdrew from each study for any reason. RESULTS: Odds ratios (95% confidence intervals) relative to placebo for 50% responders were 2.29 (1.53 to 3.43) for gabapentin, 2.32 (1.47 to 3.68) for lamotrigine, 3.03 (2.01 to 4.58) for tiagabine, 4.22 (2.80 to 6.35) for topiramate, 3.68 (2.45 to 5.51) for vigabatrin, and 2.47 (1.36 to 4.47) for zonisamide. Odds ratios for withdrawal were 1.36 (0.75 to 2.49) for gabapentin, 1.19 (0.79 to 1.79) for lamotrigine, 1.81 (1.21 to 2.70) for tiagabine, 2.42 (1.43 to 4.11) for topiramate, 2.58 (1.26 to 5.27) for vigabatrin, and 5.70 (1.76 to 18.49) for zonisamide. Comparing results for each drug showed that all of the 95% confidence intervals overlapped, indicating that they were not significantly different in terms of efficacy and tolerability. CONCLUSIONS: All six drugs were significantly better than placebo at reducing frequency of seizures. These results do not allow an evidence based choice between these drugs as we have no conclusive indication of differences in efficacy or tolerability.     

Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis

BackgroundEncephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy.ResultsDuring the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects.ConclusionsChildren with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy.     

Guidelines for treating epilepsy in the age of felbamate,vigabatrin, lamotrigine,and gabapentin.

For the first time in 15 years, new antiepileptic medications are available for the treatment of patients with seizure disorders. These drugs have demonstrated efficacy in animal models of epilepsy and in controlled clinical trials. Felbamate was licensed in 1993 for use as adjunctive therapy or monotherapy in adults with partial or tonic-clonic seizures and as adjunctive therapy for children with the Lennox-Gastaut syndrome. Gabapentin was approved January 1994 as adjunctive therapy in patients 12 years or older with partial seizures, with or without secondary generalization. Lamotrigine is expected to be approved this year for the treatment of partial and tonic-clonic seizures in adults. Last, a new drug application has been filed for vigabatrin this year, with possible licensing next year. These four anticonvulsants present new options in the treatment of patients with refractory epilepsy and are not merely congeners of previously available treatments. They have unique clinical spectrums and are reported to be safer and better tolerated than conventional therapy. Trials to compare their use with that of conventional therapy have not been done, and their use in the initial treatment of patients with epilepsy is not completely clear.     

Sex hormones in patients with epilepsy-hormonal changes in epileptic men and women taking antiepileptics.

The relationship between epilepsy and endocrine system has attracted the attention of investigators for a number of years. Epilepsy is a common neurological disorder; both seizures and antiepileptic drugs can compromise the physical and hormonal aspects of sexual development. Impairment of libido and sexual potency have been frequently reported in male epileptic patients. Women with epilepsy have a greater risk of infertility (anovulatory cycles and polycystic ovary syndrome). This review analyses the main data from the literature in order to clarify the role of epilepsy and antiepileptic drugs on sex hormones in epileptic patients. As gonad dysfunction is frequently observed in women and men with epilepsy, particularly when taking antiepileptic drugs, ovarian and testicular function must be carefully monitored.     

Reduction in polypharmacy for epilepsy.

A two-year prospective study of 40 adult outpatients with chronic epilepsy was carried out in which blood drug concentrations were monitored, and anticonvulsant polypharmacy was reduced to treatment with a single drug in 29 patients (72%). In the year after the reduction of treatment the control of seizures was improved in 16 patients (55%), unchanged in eight(28%), and worse in five (17%). Mental function was improved in 16 (55%). The main reason for failure to reduce to or maintain treatment with a single drug was exacerbation of seizures during the difficult withdrawal period, especially in patients with frequent seizures, taking several drugs, or with additional neuropsychological handicaps. It is more difficult to reduce polypharmacy than to avoid it in the first place. Polypharmacy may sometimes aggravate control of seizures.     

Intelligence and physical features of children of women with epilepsy

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6-l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy.     

Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders

Nesfatin-1 and ghrelin are the two recently discovered peptide hormones involved in the control of appetite. Besides its main appetite-control function, ghrelin also has anticonvulsant effects, while nesfatin-1 causes depolarization in the paraventricular nucleus (PVN). The aims of this study, therefore, were to investigate: (i) whether there are differences in the concentrations of nesfatin-1 and ghrelin in saliva and serum samples between eplilepsy patients and normal controls and (ii) whether salivary glands produce nesfatin-1. The study included a total of 73 subjects: 8 patients who were newly diagnosed with primary generalized seizures and had recently started antiepileptic drug therapy; 21 who had primary generalized seizures and were continuing with established antiepileptic drug therapy; 24 who had partial seizures (simple: n = 12 or complex: n = 12) and were continuing with established antiepileptic drug therapy; and 20 controls. Salivary gland tissue samples were analyzed for nesfatin-1 expression by immunochemistry and ELISA. Saliva and serum ghrelin levels were measured by ELISA and RIA, and nesfatin-1 levels by ELISA. Nesfatin-1 immunoreactivity was detected in the striated and interlobular parts of the salivary glands and the ducts. The nesfatin-1 level in the brain was around 12 times higher than in the salivary gland. Before antiepileptic treatment, both saliva and serum nesfatin-1 levels were around 160-fold higher in patients who are newly diagnosed with primary generalized epilepsy (PGE) than in controls; these levels decreased with treatment but remained about 10 times higher than the control values. Saliva and serum nesfatin-1 levels from patients with PGE and partial epilepsies who were continuing antiepileptic drugs were also 10-fold higher than control values. Serum and saliva ghrelin levels were significantly (twofold) lower in epileptic patients before treatment than in controls; they recovered somewhat with treatment but remained below the control values. These results suggest that the low ghrelin and especially the dramatically elevated nesfatin-1 levels might contribute to the pathophyisology of epilepsy. Therefore, serum and saliva ghrelin and especially the remarkably increased nesfatin-1 might be candidate biomarkers for the diagnosis of epilepsy and for monitoring the response to anti-epileptic treatment.     

A model for managing epilepsy in a rural community in Africa.

As most Malawians with epilepsy consider treatment of seizures to be the domain of traditional healers and attend hospital only when they require treatment for burns which they suffer during fits, steps were taken to encourage people with epilepsy to attend hospital for regular treatment with anticonvulsant drugs. At first only a few patients attended, but within two years 461 had registered at the hospital and two mobile clinics. Publicity was spread through the area action committee, which was organised by the area chief. The main drug used was phenobarbitone. After treatment was given for six months seizures were fully controlled in 40 (56%) out of 71 patients. A further 20 (28%) had greatly improved. As news of the clinics spread other health units adopted the model, and eventually over 3000 patients with epilepsy were receiving regular treatment at 45 units throughout Malawi.     

儿科抗癫痫药物应用研究进展

儿童癫痫为小儿神经科的常见疾病,临床表现以抽搐为主。近年来,随着医疗技术的发展,以及人们对儿童癫痫的重视,国内外文献对儿科癫痫的治疗报道越来越多,目前,药物治疗仍然是抗癫痫的首选方法,除了运用新型抗癫痫药物外,也有采用中药治疗癫痫的报道,现就近年来儿童癫痫的药物治疗研究作一综述。     

Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.     

膜超极化激活离子通道及其靶向抗癫痫药物研究进展

癫痫是一种较为常见的神经系统疾病,主要以大量神经元同步异常放电为特征。目前普遍认为,神经元或神经网络兴奋性和抑制性 电信号传输的失衡,是癫痫发病的最根本原因。现有的抗癫痫药物主要以钠离子通道、钙离子通道、钾离子通道、谷氨酸受体和γ-氨基丁 酸离子通道为靶点,但接受这些药物治疗后,仍有近1/3的病人无法控制癫痫发作。因此,抗癫痫药物的研发亟需新靶点和新思路。许多 研究证据表明,膜超极化激活离子通道的基因突变可以导致遗传型癫痫的发作,且在脑部损伤后,膜超极化激活离子通道会发生表达水平、 通道生物物理学性质及通道亚基构成的改变,从而增加神经元和神经网络兴奋性,促使癫痫发病。故近年来,膜超极化激活离子通道及其 靶向抗癫痫药物研究引起人们广泛关注。综述膜超极化激活离子通道与癫痫发病之间的关系,并探讨以膜超极化激活离子通道为靶点进行 抗癫痫药物开发和治疗的可行性。     

Strengthening the Case for Epilepsy Drug Development: Bridging Experiences from the Alzheimer’s Disease Field—An Opinion

Given the sheer number of drugs (over 20!) available for treatment of seizures, epilepsy can be considered one of the most successful areas in pharmaceutical development and especially for neuroscience. However, despite the large number of drug treatment options available for managing patients with epilepsy, there remains considerable unmet need. For example, the overall impact on seizure control has not been substantial with approximately 30% of patients remaining refractory or their seizures not adequately controlled. Also there is need for epilepsy prevention and for certain sub-populations with severe intractable epilepsy. High unmet need often drives new industry investment into therapeutic market opportunities, however the profound success of antiepileptic drugs has contributed to the hurdles for industry investment in new therapies for epilepsy. Furthermore, the payor environment has also changed with new challenges for evidence generation and demonstration of additive value above existing standard of care treatments. Challenges in translational science, in the clinical trial environment including cost and operational technical difficulty, and in the commercial environment have resulted in the pharmaceutical industry directing investments away from epilepsy into other therapeutic areas such as oncology and immunology as opportunities for higher probabilities of success and returns of investment. The neuroscience area in general is perceived a high risk area and a notable exception has been the active industry involvement in Alzheimer’s disease (AD), especially for therapeutics that could modify the course or prevent AD. AD is a very high risk area with no successful efficacious treatments found to date despite recent failures, there remains promise that therapies are forthcoming. The promise is fueled by a number of innovative factors that reduced R&D challenges in the AD field and contributed to a high level of drug development activity and investment. This paper addresses hurdles facing epilepsy drug discovery and development and focuses on some key solutions that could be eased to facilitate industry interest. Similarities in drug development challenges provide opportunities that bridge experiences and learnings from AD to epilepsy. Overall, the epilepsy field is probably in a good position for advancing into the next generation therapeutics of antiepileptic drugs targeted for increased efficacy in refractory epilepsy and for antiepileptogenesis.

     

Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal.

We tested the efficacy and safety of oral phenobarbital loading, 120 mg/h until the end-point of mild intoxication is reached, for the treatment of hypnosedative withdrawal in 48 physically dependent patients, 14 of whom had a history of withdrawal seizures. None of the patients experienced seizures or any other symptoms of withdrawal during the study period, regardless of the phenobarbital half-life. The phenobarbital loading technique can be used in any hospital, not only those with access to specialized drug analysis laboratories. The method of treatment we describe allows the clinician to focus on issues such as rehabilitation instead of drug administration and manipulation of doses.     

Long term antithyroid drug therapy for intractable cases of Graves' disease.

Among the 504 patients with Graves' disease in whom the author initiated antithyroid drug therapy between 1956 and 1968 are 14 to whom the administration of antithyroid drug has been continued for 8 to 21 years because of recurrence shortly after the discontinuation of drugs. During these periods, no side effects were observed and three patients went into complete remission after 8, 9 and 20 years of antithyroid drug administration, respectively. It is suggested therefore that the long term administration of antithryoid drugs can be a useful treatment for intractable cases.     

Novel mechanisms of action of three antiepileptic drugs,vigabatrin, tiagabine,and topiramate

Epilepsy, a functional disturbance of the CNS and induced by abnormal electrical discharges, manifests by recurrent seizures. Although new antiepileptic drugs have been developed during recent years, still more than one third of patients with epilepsy are refractory to treatment. Therefore, the search for new mechanisms that can regulate cellular excitability are of utmost importance. Three currently available drugs are of special interest because they have novel mechanisms of action and are especially effective for partial onset seizures. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA. Tiagabine is a potent inhibitor of GABA uptake into neurons and glial cells. Topiramate is considered to produce its antiepileptic effect through several mechanisms, including modification of Na⁺ -and/or Ca²⁺-dependent action potentials, enhancement of GABA-mediated Cl^– fluxes into neurons, and inhibition of kainate-mediated conductance at glutamate receptors of the AMPA/kainate type. This review will discuss these mechanisms of action at the cellular and molecular levels.     

Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients

Over-expression of efflux transporter P-glycoprotein (PgP) encoded by ABCB1 gene has been implicated in poor responsive epilepsy. Several genetic variants have been shown to influence the expression levels of P-glycoprotein. The aim of the present study was to investigate the role of ABCB1 polymorphisms: C1236T, G2677T/A and C3435T in determining drug response to first line antiepileptic drugs (AEDs) namely phenobarbitone, phenytoin, carbamazepine and valproate in North Indian cohort of epilepsy patients. DNA samples were obtained from 392 consecutive epilepsy patients, out of which 228 had completed follow-up evaluation at 12 months. After attaining steady state of the AEDs in the first two months of study, 133 patients showed complete freedom from seizures (no-seizure group) and 95 patients continued to have seizures (recurrent-seizures group) in the remaining period of study. Comparison of “no-seizure” and “recurrent-seizures” groups revealed no significant differences in allelic, genotypic and haplotypic frequencies for all the studied variants. In conclusion, our finding disproves a general association between ABCB1 polymorphisms and drug response in epilepsy patients.     

Synchrotron X-ray microbeams: A promising tool for drug-resistant epilepsy treatment

Epilepsy is one of the most important neurological diseases. It concerns about 1% of the population worldwide. Despite the discovery of new molecules, one third of epileptic patients are resistant to anti-epileptic drugs and among them only a few can benefit from resective surgery. In this context, radiotherapy is an interesting alternative to the other treatments and several clinical devices exist (e.g., Gamma Knife^®). The European Synchrotron Radiation Facility offers the possibility to develop new methods of radiosurgery and to study their antiepileptic effects. Here, we discuss several studies that we performed recently to test and try to understand the antiepileptic effects of X-ray synchrotron microbeams in different animal models of epilepsy. We showed a decrease of seizures after Interlaced Microbeam Radiotherapy (IntMRT) of the somatosensory cortex, known as the seizure generator, in a genetic model of absence epilepsy. These antiepileptic effects were stable over 4 months and with low tissular and functional side-effects. The irradiated pyramidal neurons still displayed their physiological activity but did not synchronize anymore. We also obtained a lasting suppression of seizures after IntMRT of the dorsal hippocampus in a mouse model of mesiotemporal lobe epilepsy. However, an important variability of antiepileptic efficiency was observed probably due to the small size of the targeted structure. Despite these encouraging proofs-of-concepts, there is now a need to adapt IntMRT to other models of epilepsy in rodents which are close to refractory forms of epilepsy in human patients and to implement this approach to non-human primates, before moving to clinical trials.