Adverse effects of antiepileptic drugs on bone mineral density in children

Bone mineral content (BMC) or density (BMD) may be decreased in children with epilepsy either as a consequence of the epilepsy, the condition that caused the epilepsy or the treatment for epilepsy. This paper investigates the effects of antiepileptic drugs (AEDs) on BMD in children. A systematic search of Pubmed resulted in 14 papers that described changes in BMD in children on AEDs. For phenytoin, one study failed to show a decrease in femur BMD, whereas another study reported a decrease in total body and spine BMD, but only with the use of phenytoin for > 2 years. With phenytoin combined with a ketogenic diet, a decrease in forearm BMC was seen. For phenobarbital, one study showed a decrease in spine and total body BMD, but only among those who had used phenobarbital for > 2 years. Six studies were available for carbamazepine, and none of these showed a decrease in BMD in any skeletal site. For valproate, results were diverse; two studies reported a decrease in spine BMD, whereas two other studies did not. Two studies reported a decrease in hip BMD with valproate, whereas one did not. All three studies on forearm BMD in users of valproate described a decrease. Three studies reported an improvement in BMC with vitamin D supplementation in children on AEDs. No reports on changes in BMD among users of newer AEDs are available. In conclusion, more evidence is needed for the effects on BMD in children, especially for newer AEDs. The available studies have all been cross-sectional, and longitudianal studies are needed along with studies on potential interventions in children with decreased BMD.     

Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders

Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.     

Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs

Occurring in up to 80% of patients with epilepsy, depression in epilepsy may manifest as (i) major depressive disorder, meeting Diagnostic and Statistical Manual, 4th edition (DSM-IV) diagnostic criteria; (ii) atypical depression or dysthymia; or (iii) a dysthymic-like disorder with intermittent symptoms that can be milder than those of major depression. Depressive symptoms impair patients' health-related quality of life and may affect the clinical course of epilepsy. Depressive symptoms in epilepsy have been attributed to several causes, including endocrine and/or metabolic effects of seizures; the psychological response to epilepsy and its associated mental, physical and social challenges; common pathogenic mechanisms between depression and epilepsy; and the adverse effects of certain antiepileptic drugs (AEDs), particularly GABAergic agents, such as vigabatrin, tiagabine, topiramate and phenobarbital. Whereas some AEDs impair mood, others appear to improve aspects of mood or are mood neutral. Demonstrable antidepressant efficacy of AEDs used to manage seizures could have a significant impact on the care of patients with epilepsy. The AED lamotrigine has been demonstrated to be effective in the treatment of depressive symptoms in patients with epilepsy. In randomized, double-blind, clinical trials in patients with epilepsy, depressive symptoms improved more with lamotrigine monotherapy than valproate monotherapy and more with lamotrigine adjunctive therapy than placebo. Results of open-label studies of lamotrigine monotherapy and adjunctive therapy are consistent with the results of double-blind clinical trials. Lamotrigine-associated improvement in depressive symptoms is independent of its anticonvulsant efficacy. In prospective assessments, gabapentin, levetiracetam and oxcarbazepine each exhibited potentially beneficial effects on depressive symptoms in patients with epilepsy. However, evidence for the efficacy of gabapentin, levetiracetam and oxcarbazepine in the treatment of depressive symptoms in epilepsy is inconclusive at present because the effects of each agent have only been reported in single studies of an open-label design and with small sample sizes.     

Assessment of drug–drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I₁-imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.     

Simple febrile convulsions in children: explain and reassure the parents

(1) Simple febrile convulsions (brief and generalised) in children carry a high risk of recurrence during new febrile episodes (30-50%), especially while the child is under the age of 3 years. These relapses are rarely severe and only occur during a minority of febrile episodes. Later onset of epilepsy is rare. (2) Long term treatment with phenobarbital and valproic acid reduce the risk of relapse but carry a risk of bothersome or severe adverse effects. These treatments are rarely warranted in this setting. (3) Oral diazepam administration to a febrile child has moderate preventive efficacy, which is further limited by the difficulty of timing the treatment correctly. Oral diazepam has frequent but generally mild adverse effects. (4) Antipyretics are not very effective at preventing febrile convulsions but can make the child more comfortable. (5) Parents are often upset when they first see their child have a febrile convulsion. It is important to take the time to reassure them.     

Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from na?ve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter "severity" offered important additional information about the drug profile that would otherwise be lost if only a single parameter as "incidence" was used.     

A comparative study of the efficacy of newer antiepiletpic drugs on experimentally-induced febrile convulsions.

In mice subjected to microwave diathermy, four new antiepileptic drugs were compared to phenobarbital for efficacy against experimentally induced febrile convulsions. Carbamazepine (10–50 mg/kg) and clonazepam (0.05–0.10 mg/kg) were ineffective against febrile seizures. Dipropylacetic acid (100–400 mg/kg) exerted effects similar to those of phenobarbital. N,N¹-dimethoxymethyl-pheno-barbital (DMMP) elevated the febrile convulsive temperature threshold, depressed the rate of rise of body temperature, and decreased the intensity of the convulsion. At a dosage of 50 mg/kg, DMMP was more protective than phenobarbital (P < 0.001) in raising the convulsive threshold and in retarding the rate of rise of body temperature (P < 0.01). These antiepileptic effects of DMMP occurred at relatively non-toxic doses ( 10–200 mg/kg).     

MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响

目的在大鼠杏仁核点燃模型研究MK-801(地佐西平)及其联合用药的抗癫痫作用。方法建立大鼠杏仁核慢性电刺激点燃模型,测定不同剂量的MK-801对点燃模型各项指标的影响,探讨MK-801与其他抗癫痫药的协同作用,用氨基脲诱发的小鼠惊厥模型测定MK-801抗惊厥作用。 结果MK-801(0.1～0.25 mg·kg^-1)可剂量依赖性抑制杏仁核点燃,缩短后放电时程,降低Racine's分级;在对点燃均无明显影响的剂量下,MK-801(0.05 mg·kg^-1)与抗癫痫药(苯巴比妥、丙戊酸及尼卡地平)合用可缩短后放电时程或降低Racine's分级。MK-801(0.1～0.25 mg·kg^-1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率。结论MK-801具有抑制大鼠杏仁核点燃的作用,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性,为临床的合并用药提供实验依据。     

Prevention and management of febrile seizures

Febrile seizures are the most common seizures in childhood and, like all seizures, can be frightening to witness. Therefore, it is not surprising that febrile seizures have been the focus of intense research with an extensive literature describing various preventative measures. In addition, there is also an extensive and sophisticated epidemiological literature delineating the natural history of this disorder in American and British children. For simple febrile seizures, the most common form of this disorder, the epidemiological studies demonstrate a generally benign natural history, making it unlikely that any preventative measure could improve the long term outcome for most children. Children with simple febrile seizures have a slight increased risk of epilepsy, but there are no studies that demonstrate that phenobarbital or other therapy can alter this risk. Daily therapy with phenobarbital or valproic acid can reduce the number of subsequent simple febrile seizures. However, as a recent Practice Parameter from the American Academy of Paediatrics concludes, the risk of adverse effects from daily therapy appears to outweigh the benefit of preventing the short term recurrence of simple febrile seizures. It is possible that in some families, where the occurrence of an additional simple febrile seizure would be particularly distressing, the routine use of oral diazepam during febrile illnesses might be appropriate.     

Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs

Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs–induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.     

Ion channels and epilepsy

The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.     

Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: a comparative review of newer versus older agents

Several 'new' antiepileptic drugs (AEDs), i.e. oxcarbazepine, vigabatrin, lamotrigine, zonisamide, gabapentin, tiagabine, topiramate and levetiracetam have been introduced into clinical practice within the last decade. Most of these new drugs are at least as effective as the 'old' AEDs [phenytoin, phenobarbital (phenobarbitone), valproic acid (sodium valproate) and carbamazepine] and, in general, they seem to be better tolerated than the old drugs. The new AEDs might have less influence on cognitive functions but the aspect has not been systematically studied. Neuropsychological testing has been the major method of objectively examining cognitive function related to the use of AEDs but a number of methodological problems blur the results. Alteration of cognition might reflect a chronic adverse effect of AEDs but the negative effects of the drugs are only one of several factors that may influence cognition. In addition, subjective complaints about cognitive deficits (e.g. memory problems or attention) may also reflect other aspects of adverse effects than those concerning specific cognitive functions (e.g. mood and anxiety). This review focuses on studies of the cognitive effects of the new AEDs, and in particular on studies that compare cognitive effects of the old and new drugs. In general, the new AEDs seem to display no or minor negative cognitive effects. In studies in which new AEDs have been compared with old AEDs, there was a tendency in favour of the new AEDs in some of the studies.     

Prescribing antiepileptics for the elderly: differences between guideline recommendations and clinical practice

The incidence of epilepsy in patients aged >60 years is higher than in any other period of life. Yet, until recently, what was known about the treatment of older patients with epilepsy has been inferred from studies in younger patients. A growing body of clinical evidence focused exclusively on the elderly suggests that, while some issues are similar for older and younger adults, older patients with epilepsy may require even more attention regarding antiepileptic drug (AED) selection than younger patients. This article reviews published guidelines and recommendations to identify explicit recommendations for use of specific AEDs in the elderly, and assesses the extent to which those recommendations have been adopted in clinical practice.We found that while one systematically derived guideline stated that lamotrigine may be a good choice for older patients because of its favourable adverse effect profile, only clinical recommendations based on expert opinion explicitly identified AEDs that are more and less appropriate for use in the elderly. Examination of published studies describing recent AED-prescribing patterns suggests that clinical recommendations have been, at best, slowly adopted. This observation is exemplified by the fact that older patients newly diagnosed with epilepsy are still prescribed phenobarbital--a drug identified as suboptimal in 1985.In order to better understand the delay in adopting clinical recommendations, we examine these findings in light of diffusion of innovations theory, a theory that has been used to understand dissemination of other new medical technologies. According to this theory, while it is too early to suggest that use of second-generation AEDs in the elderly has been delayed, the continued use of phenobarbital in older patients newly diagnosed with epilepsy represents a serious delay in adoption of recent guidelines. Delays may be related to lack of knowledge by primary care clinicians and emergency room physicians (who frequently treat older patients with epilepsy), lack of 'opinion leaders' in primary care and perhaps general neurology, clinicians' focus on seizure control as the primary endpoint in treating patients with epilepsy, and difficulties in changing long-standing prescribing patterns.Research targeting barriers to more appropriate prescribing is needed to determine appropriate strategies for changing AED prescribing practices in the elderly.     

Methodologies used to identify and characterize interactions among antiepileptic drugs

Polytherapy antiepileptic drug (AED) regimens are prevalent in the treatment of epilepsy and the potential for AEDs to interact results in many challenges. Understanding the underlying mechanism of an interaction, along with the magnitude and its time course of presentation can allow a graded and informed therapeutic adjustment so as to minimize the adverse consequences (breakthrough seizures, increased adverse effects) of the interaction. The purpose of the present review is to address the importance of characterizing interactions among AEDs and to emphasize how preclinical studies, both in vitro and in animal models, can help inform the design of clinical studies and the characterization of potential interactions in patients with epilepsy. In addition, we review and discuss methodological issues of how case studies, population pharmacokinetic data and data from therapeutic drug-monitoring databases can provide invaluable signals regarding potential interactions that have yet to be investigated in formal clinical trials.     

Pharmacotherapy for children and adolescents with epilepsy

INTRODUCTION: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25-30% of children with epilepsy remain refractory to medical therapy. AREAS COVERED: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability. EXPERT OPINION: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and--subsequently--as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilepsy in children.     

Several major antiepileptic drugs are substrates for human P-glycoprotein

One of the current hypotheses of pharmacoresistant epilepsy proposes that transport of antiepileptic drugs (AEDs) by drug efflux transporters such as P-glycoprotein (Pgp) at the blood-brain barrier may play a significant role in pharmacoresistance in epilepsy by extruding AEDs from their intended site of action. However, several recent in vitro studies using cell lines that overexpress efflux transporters indicate that human Pgp may not transport AEDs to any relevant extent. In this respect it has to be considered that most AEDs are highly permeable, so that conventional bi-directional transport assays as used in these previous studies may fail to identify AEDs as Pgp substrates, particularly if these drugs are not high-affinity substrates for Pgp. In the present study, we used a modified transport assay that allows evaluating active transport independently of the passive permeability component. In this concentration equilibrium transport assay (CETA), the drug is initially added at identical concentration to both sides of a polarized, Pgp-overexpressing cell monolayer instead of applying the drug to either the apical or basolateral side for studying bi-directional transport. Direct comparison of the conventional bi-directional (concentration gradient) assay with the CETA, using MDR1-transfected LLC cells, demonstrated that CETA, but not the conventional assay, identified phenytoin and phenobarbital as substrates of human Pgp. Furthermore, directional transport was determined for lamotrigine and levetiracetam, but not carbamazepine. Transport of AEDs could be completely or partially (>50%) inhibited by the selective Pgp inhibitor, tariquidar. However, transport of phenobarbital and levetiracetam was also inhibited by MK571, which preferentially blocks transport by multidrug resistance transporters (MRPs), indicating that, in addition to Pgp, these AEDs are substrates of MRPs. The present study provides the first direct evidence that several AEDS are substrates of human Pgp, thus further substantiating the transporter hypothesis of pharmacoresistant epilepsy.     

Behavioral adverse effects of antiepileptic drugs in epilepsy

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.     

Tiagabine

Tiagabine inhibits gamma-aminobutyric acid uptake into neurons and glia. This mechanism of action is specific and unique among the antiepileptic drugs (AEDs). Tiagabine is efficacious in animal seizure models at subtoxic doses. There is no evidence of clinically important teratogenicity, carcinogenicity or mutagenicity in animals treated acutely or chronically with tiagabine. Tiagabine has no clinically relevant effect on hepatic metabolism or serum levels of other AEDs, has no clinically significant effects on laboratory values and has not been shown to have any clinically important interactions with common non-AEDs. Tiagabine has linear, predictable pharmacokinetics that do not vary significantly with age. Adverse effects are usually mild to moderate in severity and almost always resolve without medical intervention. The most common adverse events in controlled studies are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea and nervousness. Tiagabine is effective as add-on therapy for partial seizures in patients with medically refractory epilepsy in doses ranging from 32-56 mg daily. Despite its short half-life of 2-3 hours in patients on enzyme-inducing AEDs, tiagabine is effective when dosed 2-3 times a day. Conversion to tiagabine monotherapy can be achieved in patients with medically refractory epilepsy, though additional studies are needed to establish the effective dosage range. The introduction of drugs like tiagabine that have known mechanisms of action which differ from existing treatments further increases the range of options for patients with epilepsy.     

Current issues in the treatment of epilepsy

General principles of antiepileptic drug (AED) therapy are reviewed, current issues involving the use and monitoring of AEDs are examined, promising investigational agents are briefly reviewed, and situations that require potentially difficult decisions about long-term care are discussed. The initial treatment should be monotherapy with a first-line AED for the particular seizure disorder. The usual approach is to maximize seizure control and minimize the adverse effects of AED therapy. Current issues involving the pharmacokinetics, use, and monitoring of the conventional AEDs phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, ethosuximide, benzodiazepines, and acetazolamide are discussed. AED therapy may have adverse effects on behavior and cognition. The risk of teratogenicity with well-monitored AED therapy is probably low, and severe hepatotoxicity is uncommon. Because carbamazepine, phenobarbital, phenytoin, and primidone all have enzyme induction properties, a number of clinically important interactions are possible. Issues related to discontinuing AED therapy, serum concentration monitoring, and generic interchange of AED products are addressed. Whether AEDs should be used to prevent recurrent febrile seizures, alcohol withdrawal seizures, or seizures in patients with head trauma or stroke must be considered. The treatment of seizure disorders is a complex process involving identification of the seizure disorder, selection and monitoring of an appropriate AED(s), and consideration of adverse effects and drug interactions. Whether therapy should be discontinued after a prolonged seizure-free period, compliance issues, and whether to treat certain conditions prophylactically also must be considered.     

Gabapentin and lamotrigine: novel antiepileptic drugs.

The pharmacokinetics, efficacy, and adverse effects of gabapentin and lamotrigine, two new antiepileptic drugs (AEDs), are reviewed. Gabapentin and lamotrigine are promising advances in the treatment of epilepsy, which has not been satisfactorily controlled by available agents in 25-41% of patients. Gabapentin is chemically similar to gamma-aminobutyric acid, but it is able to pass into the central nervous system. It is effective for the treatment of partial-onset seizures that are refractory to other AEDs. It has no known drug-drug interactions and a relatively benign adverse effect profile, but its short half-life necessitates at least thrice-daily dosing. Lamotrigine is structurally unrelated to the other available AEDs. Its role is currently limited to add-on therapy in patients with partial seizures, with or without secondary generalization, that are resistant to current treatment. The efficacy of lamotrigine in patients with primary generalized tonic-clonic seizures, absence seizures, and Lennox-Gastaut syndrome remains to be validated. The adverse effect profile also remains to be determined. A rash may appear in up to 5% of patients, possibly necessitating discontinuation of the drug. Although lamotrigine does not seem to affect the pharmacokinetics of the other AEDs, the other AEDs affect lamotrigine pharmacokinetics. Lamotrigine can be given once or twice daily. Gabapentin and lamotrigine may be useful in treating patients whose epilepsy is not controlled by other available AEDs; however, further research is needed to confirm their roles in epilepsy treatment.