Newer antiepileptic drugs]

Ten newer antiepileptic drugs have been developed since 1990s. These drugs have wider therapeutic spectra, fewer side-effects, and lesser drug-to-drug interactions compared with the older typical antiepileptic drugs. Among them, zonisamide was developed in Japan and has been used from 1989. Gabapentin was at length approved in 2006. The other newer antiepileptic drugs are not approved yet in Japan. Felbamate can not be used in Europe because it may induce lethal hepatic toxicity and aplastic anemia. Vigabatrin is not approved in USA because it may induce permanent visual field deficit. The USA guideline for epilepsy treatment recommends that patients with newly diagnosed epilepsy can be treated with gabapentin, lamotrigine, topiramate, and oxcarbazepine. In contrast, based on epilepsy treatment guideline in England, newer antiepileptic drugs are considered only when patients with newly diagnosed epilepsy are unable to use the older antiepileptic drugs for some reasons. All newer antiepileptic drugs are used for intractable partial epilepsies, and lamotrigine and topiramate can also be used for idiopathic generalized epilepsies. The response rate (seizure reduction rate with 50% or more) and drop-out rate are overlapping among all newer antiepileptic drugs. Gabapentin, levetiracetam, and pregabalin are eliminated from kidney, and they had no drug-to-drug interactions and can be titrated rapidly. The serum concentration of lamotrigine is decreased with co-administration of hepatic enzyme inducing drugs and is increased with co-administration of valproic acid. Hypersensitivity reactions are rare with gavapentin, levetiracetam, topiramate, and tiagabin. Psychoses are reported to be induced with zonisamide, however, they can be induced with the other newer drugs (topiramate, levetiracetam, etc.). Drug-induced psychiatric symptoms, especially depression, may be often underdiagnosed. Many of these newer drugs (gabapentine, lamotrigine, levetiracetam, oxycarbazepine, etc.) have effects on chronic neuropathic pain. Some newer drugs show mood stabilizing effects (lamotrigine, oxycarbazepine, etc.), or antianxiety effect (gabapentin, topiramate, levetiracetam, pregavalin, etc.). Wide range of action to central nervous system of these newer antiepileptic drugs may serve not only for clinical seizure suppression, but also for neuroprotection.     

Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use

A prospective study of the efficacy of seizure cessation by phenobarbital versus phenytoin administration utilized both clinical and electroencephalographic expressions of seizure behaviors. The phenomenon of uncoupling was defined as the persistence of electrographic seizures despite the suppression of >or=50% clinical seizures after either one or both antiepileptic drugs use. Fifty-nine neonates (25 to 43 weeks estimated gestational age) with electrically-confirmed seizures were assigned to either of two drugs and continuously monitored over a 24-hour period. Nine of the fifty-nine patients had only electrographic seizure expression both before and after drug administration. Of the remaining 50 patients who had both electrical and clinical seizure expression before treatment, 24 infants responded to the first choice of an antiepileptic drug with no further seizures. Fifteen of the remaining 26 infants (58%) with persistent seizures after treatment had uncoupling of electrical and clinical expressions of seizures; no difference in the uncoupling effect was noted for neonates who were treated with either antiepileptic drug or based on prematurity or gender. Serial electroencephalographic monitoring helps document continued electrographic seizure expression after antiepileptic drug use, following complete or partial suppression of clinical seizure behaviors.     

Suppression of antiepileptic treatment

The present report evaluates the suppression of antiepileptic drugs in a group of 608 epileptics. Conditions for the suppression of antiepileptic treatment included a previous seizure-free period of 5 years under medication, and a careful evaluation of individual social and work-related circumstances. The reduction of medication was realized during a minimum period of 1 year, passing from eventual polytherapy to monotherapy. Of the total 608 epileptics in whom treatment was suppressed, 144 relapses (23.7%) occurred, and 464 (76.3%) patients continued to be seizure-free. A complete remission of the epilepsy was achieved in 14.3% of 3,254 epileptics with an adequate follow-up. Significant risk factors for recurrence included a delay in starting anticonvulsant therapy; symptomatic generalized epilepsy; different types of combined seizures, or atypical absences and/or tonic crisis and/or atonic crisis; or partial complex associated with secondary generalized tonic-clonic seizures; the presence of status epilepticus in the course of the disease and permanent neurologic damage. With the patient's prior agreement, it was possible to suppress anticonvulsant medication in one fourth of nonselected epileptic patients with a possibility of relapse in about 25% of the cases (generally one isolated seizure).     

Teratogenic effects of antiepileptic drugs

Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed.     

抗癫痫药性脑病

抗癫痫药性脑病作为抗癫痫药物的副作用，临床上并不多见，医生往往缺乏足够认识。本综述了常用抗癫痫药物所致脑病的临床特点、危害、可能发生机制、处理及预后，以引起人们应有的重视。     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Mechanisms of antiepileptic drug action

Animal seizure models, in vitro preparations of cell cultures and tissue slices, and an unravelling of some of the basic mechanisms underlying epileptogenesis and epilepsy have furthered the understanding of mechanisms of action of antiepileptic drugs at the cellular and subcellular levels. Nevertheless, the mechanism of action of most antiepileptic drugs in clinical use is incompletely understood. Multiple physiologic mechanisms are altered by antiepileptic drugs. Some of these drugs, such as phenytoin and carbamazepine, decrease sustained repetitive firing and post-tetanic potentiation through their blocking effects on the sodium channel. Benzodiazepines and barbiturates enhance GABA-mediated inhibition. Many antiepileptic drugs inhibit calcium influx and calcium-mediated secondary effects at supratherapeutic concentrations. Newer drugs that inhibit excitatory receptors or enhance various forms of inhibition are presently under investigation.     

Discontinuation of antiepileptic drugs after pediatric epilepsy surgery

In children with medically intractable seizures, epilepsy surgery is now a widely accepted option. Successful discontinuation of antiepileptic drugs after epilepsy surgery has been reported in adults, but rarely in children. Surgical outcome and need for antiepileptic drugs after temporal and extratemporal lobe resection were retrospectively reviewed for 80 pediatric patients from the Comprehensive Epilepsy Program at the University of Alberta. For 1 year after surgery, children were maintained on at least one antiepileptic drug. Antiepileptic drug discontinuation was attempted in all patients with a nonepileptic electroencephalogram after 1 year seizure-free. Less than half of the patients (44%) eventually relapsed without antiepileptic drugs. Of the 40 patients in the temporal lobe group, 13 (32%) relapsed without antiepileptic drugs, as did 22 of the 40 extratemporal lobe resection patients (55%). Success rates for antiepileptic drug discontinuation after surgery were higher in the temporal lobe than in the extratemporal lobe group. Long-term antiepileptic drugs are not necessary in all cases, and for many children medication can be withdrawn after epilepsy surgery.     

Strategy for utilization of new antiepileptic drugs

PURPOSE OF REVIEW: The paper reviews strategies to incorporate new antiepileptic drugs into the treatment arsenal for patients with epilepsy. RECENT FINDINGS: Ten new antiepileptic drugs have been developed in the last two decades, making selection of optimal therapy complex; they have not been shown to have better efficacy but generally seem to be better tolerated. Newer antiepileptic drugs offer new opportunities to patients who have not had a favorable response to the old ones. Many new antiepileptic drugs exhibit a broad spectrum of activity while only one of the older ones (valproate) has a broad-spectrum profile. There are therefore more choices when trying to match treatment with epileptic seizures and syndromes. The side-effect profiles of the newer antiepileptic drugs differ from the older ones with fewer systemic reactions and better pharmacokinetics for the most part. SUMMARY: Comparative studies are needed to elucidate the specific weaknesses and strengths of each of the new antiepileptic drugs compared with the older ones. Most clinical trials do not help the physician in deciding drug, dose, or titration schedules. Thus the physician needs to understand efficacy spectrum and side-effect profiles of each new antiepileptic drug in order to be able to treat each patient optimally.     

Psychotropic effect of antiepileptic drugs

Eighteen controlled studies investigating the psychotropic effect of anti-epileptic drugs are critically reviewed. The neurochemical evidence for existence of psychotropic properties is still speculative. It seems questionable on the basis of this survey that there exist genuine psychotropic effects of antiepileptic drugs, which are not related to antiepileptic efficacy and/or differences in toxicity.     

Growth suppression in children receiving acetazolamide with antiepileptic drugs

To clarify the effect of the clinical dosage of acetazolamide on growth in children with epilepsy or febrile convulsion, the standard scores of height and weight in 17 subjects receiving acetazolamide as an adjunct to unchanged monotherapy of antiepileptic drug were compared longitudinally through four phases: before antiepileptic drug administration, with monotherapy of antiepileptic drug, with acetazolamide in addition to monotherapy, and after acetazolamide discontinuation. The standard scores of both height and weight in the subjects were significantly reduced during the phase of acetazolamide administration. During this period, serum concentrations of potassium and total CO₂ decreased while that of chloride increased, suggesting the existence of metabolic acidosis in the subjects. For both height and weight, there was no correlation between the degree of standard score reduction during acetazolamide administration and age at the time of acetazolamide initiation, duration of acetazolamide administration, dosages of acetazolamide, and variety of antiepileptic drugs concomitantly administered with acetazolamide. We speculate that metabolic acidosis induced by acetazolamide suppressed the growth of the subjects and that there were large individual differences in the susceptibility to acetazolamide for growth suppression among patients receiving acetazolamide.     

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.     

Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects

Antiepileptic drugs exert their anticonvulsant effects by interfering with brain processes that involve structures that are also involved in learning, memory, and emotional behavior. Thus, modulation of ion channels, neurotransmitters, second messengers, and other processes by antiepileptic drugs, although helpful in controlling seizures, can interfere with normal brain function in undesired ways. The specific mechanism(s) of action of an antiepileptic drug can increase the risk for particular types of adverse events. In this review, we examine the cognitive and behavioral effects of antiepileptic drugs in animal models. Although animal studies, in many respects, do not mimic clinical experience, the data suggest a connection between certain mechanisms of antiepileptic action and the occurrence of cognitive adverse effects. Specifically, antiepileptic drugs with traditional gamma-aminobutyric acid (GABA)ergic mechanisms have the most detrimental effects on cognitive function, possibly because they impair attention. Conversely, drugs with the predominant effects at Na+ channels appear to have minimal impact on cognition. Levetiracetam, with its nonconventional GABAergic and Ca2+ channel effects, has shown positive cognitive effects in animal studies. Antiglutamatergic drugs have the potential to be a double-edged sword: they can interfere with consolidation of learning and memory but can also provide neuroprotection in addition to their antiseizure effects.     

Adverse effects of antiepileptic drugs

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects.     

Effect of antiepileptic drug polytherapy on crystalluria

Urolithiasis is a rare side effect of antiepileptic drugs. To clarify the risk factors for urolithiasis induced by antiepileptic drugs, the effect of antiepileptic drug monotherapy on crystalluria was studied, and zonisamide or sulthiame therapy and alkaline urine were demonstrated to be risk factors. In the next investigation, the effect of antiepileptic drug polytherapy on crystalluria was retrospectively studied in epilepsy patients treated for more than 1 month during the last 7 years. A total of 278 urine specimens from epilepsy patients aged between 7 months and 36 years were enrolled in this study. The mean age was 12.3 years. There were 109 samples from females and 169 from males. Antiepileptic drugs administered in this study were valproate (174 urinary samples), zonisamide (139), carbamazepine (138), phenobarbital (65), phenytoin (52), acetazolamide (17), clonazepam (15), sulthiame (6), ethosuximide (6), nitrazepam (4), and clobazam (4). Epilepsy patients treated with antiepileptic drug polytherapy were frequently found to have crystalluria in patients demonstrating alkaline urine and taking acetazolamide, zonisamide (particularly with high serum levels), or many antiepileptic drugs in combination. Regular urinalysis seems to be necessary in these patients, and the evaluation for urolithiasis should be performed if persistent crystalluria is demonstrated.     

Modern antiepileptic drugs: guidelines and beyond

PURPOSE OF REVIEW: Ten antiepileptic drugs have been licensed since 1990. Their usage will be briefly reviewed focusing on new data and inclusion in guidelines. The hypotheses exploring the underlying basis of pharmacoresistance will be presented. RECENT FINDINGS: Lamotrigine, gabapentin, topiramate, and oxcarbazepine are available for use as monotherapy in many countries following comparative studies with older antiepileptic drugs. Zonisamide and pregabalin have recently obtained licences as adjuvant therapy in the US and Europe for partial epilepsy with or without secondary generalization. The UK National Institute for Clinical Excellence guideline has advised, largely based on cost, against the routine use of modern antiepileptic drugs, except when older drugs have failed or are contraindicated. This contrasts with the US guidelines which are less conservative. Surgically resected specimens from patients with refractory epilepsy have led to the development of two hypotheses to explain pharmacoresistant epilepsy. SUMMARY: The introduction of 10 new antiepileptic drugs has provided greater choice for patients and doctors, although evidence in support of their superiority over the older drugs is sparse. This has led to conflicting advice in guidelines. Recent developments in the understanding of pharmacoresistance may explain the relatively high incidence of refractory epilepsy.     

Seizure-inducing paradoxical reaction to antiepileptic drugs

We report on an 18-month-old girl with a seizure frequency of five/day, receiving an antiepileptic polytherapy consisting of primidone, clonazepam and phenytoin. Following discontinuation of clonazepam and primidone, the patient has been seizure-free under monotherapy for 2 years and shows marked developmental progress. Possible mechanisms of this paradoxical effect of antiepileptic drugs and the implications for antiepileptic therapy are discussed.     

Nonepileptic uses of antiepileptic drugs in children and adolescents

Antiepileptic drugs are often prescribed for nonepileptic neurologic and psychiatric conditions. The United States Food and Drug Administration has approved several antiepileptic drugs for the treatment of neuropathic pain, migraine, and mania in adults. For pediatric patients, use of antiepileptic drugs for non-seizure-related purposes is supported mainly by adult studies, open-label trials, and case reports. Summarized here is the published literature for or against the use of antiepileptic drugs for neuropathic pain, migraine, movement disorders, bipolar disorder, aggressive behavior, and pervasive developmental disorders in children and adolescents. Using the American Academy of Neurology's four-tiered classification scheme for a therapeutic article and translation to a recommendation rating, there are no nonepileptic disorders for which antiepileptic drugs have been established as effective for pediatric patients. Valproate and carbamazepine are "possibly effective" in the treatment of Sydenham chorea, and valproate is "probably effective" in decreasing aggressive behavior. Carbamazepine is "probably ineffective" in the treatment of aggression, and lamotrigine is "possibly ineffective" in improving the core symptom of pervasive developmental disorders. Despite the frequent use of antiepileptic drugs in the treatment of juvenile bipolar disorder, migraine, and neuropathic pain, the data are insufficient to make recommendations regarding the efficacy of antiepileptics in these conditions in children and adolescents.     

Effect of antiepileptic drug monotherapy on urinary pH in children and young adults

Objects Since alkaline urine is a risk factor for urolithiasis, the relationship between antiepileptic drugs and urinary pH was retrospectively studied in epilepsy patients treated with antiepileptic drug monotherapy for more than 1 month.Methods A total of 913 urinary samples from antiepileptic drug-treated patients were compared with 780 age-matched control samples, and with 112 samples from epilepsy patients who had not been treated with antiepileptic drugs. The antiepileptic drugs administered were carbamazepine, valproate, phenobarbital, zonisamide, sulthiame, and phenytoin.Conclusions The proportion of the acid urine in the valproate-treated patients was lower than that in controls. The proportion of the alkaline urine in the valproate-treated patients was higher than that in controls. This effect was independent of age, sex, and the serum valproate concentration. There was no significant difference in urinary pH among the epilepsy patients treated with other antiepileptic drugs, the epilepsy patients who had not been treated with antiepileptic drugs, and the controls.     

Photosensitivity as a model for acute antiepileptic drug studies

A technique is described for assessing the efficacy and time course of effects of antiepileptic drugs, after a single acute dose, by means of their action on the human photo-convulsive response. The range of frequencies of intermittent photic stimulation to which the patient is sensitive (photosensitivity range) is determined in a standardized manner at hourly intervals over the course of a waking day. 82 controlled studies have established that, with the rare exceptions of patients showing a consistent circadian rhythm of photosensitivity, the photosensitivity range is stable over this time scale. A total of 72 studies have shown that representatives of all the major groups of established antiepileptic drugs, together with some experimental drugs, suppress photosensitivity following a single acute administration. By contrast barbiturates without antiepileptic action (methohexitone and quinalbarbitone) do not affect photosensitivity even in doses producing marked drowsiness. These findings suggest the technique to be a potentially useful tool for preliminary investigation of efficacy and duration of action of new potential antiepileptic drugs.