Second-generation Antiepileptic Drugs Research Articles

Drug interactions involving the new second- and third-generation antiepileptic drugs

During the period 1989–2009, 14 new antiepileptic drugs (AEDs) were licensed for clinical use and these can be subdivided into new second- and third-generation AEDs. The second-generation AEDs comprise felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. The third-generation AEDs comprise eslicarbazepine acetate and lacosamide. The interaction propensity of AEDs is very important because all new AEDs are licensed, at least in the first instance, as adjunctive therapy. The present review summarizes the interactions (pharmacokinetic and pharmacodynamic) that have been reported with the newer AEDs. The pharmacokinetic interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the liver. Overall, the newer AEDs are less interacting because their pharmacokinetics are more favorable and many are minimally or not bound to blood albumin (e.g., eslicarbazepine, felbamate, gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) and are primarily renally excreted or metabolized by noncytochrome P450 or uridine glucoronyl transferases (e.g., gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) as opposed to hepatic metabolism which is particularly amenable to interference. Gabapentin, lacosamide, levetiracetam, pregabalin and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate are the most interacting. Furthermore, the metabolism of lamotrigine is susceptible to both enzyme inhibition and enzyme induction. While the metabolism of felbamate, tiagabine, topiramate and zonisamide can be induced by enzyme-inducing AEDs, they are less vulnerable to inhibition by valproate. Noteworthy is the fact that only five new AEDs (eslicarbazepine, felbamate, oxcarbazepine, rufinamide and topiramate) interact with oral contraceptives and compromise contraception control. The most clinically significant pharmacodynamic interaction is that relating to the synergism of valproate and lamotrigine for complex partial seizures. Compared with the first-generation AEDs, the new second- and third-generation AEDs are less interacting, and this is a desirable development because it allows ease of prescribing by the physician and less complicated therapeutic outcomes and complications for patients.

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Antiepileptic drugs (AEDs) have been available for many years; yet, new members of this class continue to be identified and developed due to the limitations of existing drugs, which include a propensity for cognitive impairment. However, there is little preclinical information about the cognitive effects they produce, which clinically include deficits in attention and slowing of reaction time. The purpose of this study was to profile two first-generation AEDs, phenytoin and valproate, and three second-generation AEDs, levetiracetam, pregabalin and lacosamide. Initially, each drug was examined across a range of well characterised preclinical seizure tests, and then each drug was evaluated in the five-choice serial reaction time test (5-CSRTT) based on efficacious doses from the seizure tests. Each AED was tested for anti-seizure efficacy in either (1) the maximal electroshock seizure test, (2) s.c. PTZ seizure test, (3) amygdala-kindled seizures and (4) the genetic absence epilepsy rat of Strasbourg model of absence seizures. On completion of these studies, each drug was tested in rats trained to asymptotic performance in the 5-CSRTT (0.5 s SD, 5 s ITI, 100 trials). Male rats were used in all studies. Each AED was active in at least one of the seizure tests, although only valproate was active in each test. In the 5-CSRT test, all drugs with the exception of levetiracetam, significantly slowed reaction time and increased omissions. Variable effects were seen on accuracy. The effect on omissions was reversed by increasing stimulus duration from 0.5 to 5 s, supporting a drug-induced attention deficit. Levetiracetam had no negative effect on performance; indeed, reaction time was slightly increased (i.e. faster). These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.

Effect of ethacrynic acid on the anticonvulsant activity of the second-generation antiepileptics against maximal electroshock-induced seizures in mice

Recent experimental studies show that ethacrynic acid (ETA), a loop diuretic, exerts the anticonvulsant activity. Therefore, we tested the effect of ETA on the protective action of some second-generation antiepileptic drugs (oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) in the mouse maximal electroshock seizure (MES) model. ETA was administered acutely (50 and 100 mg/kg i.p.) or chronically, for 7 days (12.5 mg/kg i.p.). Both ETA acute (up to 100 mg/kg) and chronic (up to 12.5 mg/kg) treatment did not influence the threshold for electroconvulsions. In the MES test, ETA (100 mg/kg) potentiated the protective activity of TPM, decreasing its ED(50) value from 38.1 to 18.7 mg/kg (P<0.01). In contrast, ETA (100 mg/kg) remained without effect on the anticonvulsant action of the other antiepileptics (OXC and LTG) in mice. Chronic administration of ETA (12.5 mg/kg) did not affect the protective action of tested antiepileptics. The observed interaction between acute ETA and TPM was pharmacodynamic in nature because neither plasma nor total brain TPM concentrations were altered after injection of ETA.These results indicate existing interactions between ETA and TPM, which may have some clinical importance for epileptic patients treated with TPM and additionally ETA due to other medical causes.

Utilization of antiepileptic drugs during pregnancy: Comparative patterns in 38 countries based on data from the EURAP registry

We assessed the utilization of antiepileptic drugs (AEDs), 1999-2005, in 4,798 prospective epilepsy pregnancies from 38 countries participating in EURAP, an international AED and pregnancy registry. Prominent differences in utilization patterns were observed across the various countries. Exposure to second-generation AEDs ranged from 3.5% in India and 7.3% in Italy to 75% in Denmark. Even wider variation was recorded in exposure to individual AEDs. The utilization of second-generation AEDs increased over time (for lamotrigine, from 9.9% of all pregnancies before 2001 to 29.6% after 2003). The differences in use of individual AEDs across countries probably reflect lack of evidence concerning the optimal treatment of epilepsy in women of childbearing age, as well as variation in country-specific traditions, medication costs, and drug promotion. Our observations underscore the need for comparative studies to investigate the factors influencing the prescription of AEDs during pregnancy, as well as their influence on pregnancy outcome.

Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.

Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in miceA

The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model.The results indicate that agmatine (up to 100mg/kg, ip, 45min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED50 value of vigabatrin from 517.5 to 790.3mg/kg (p<0.01). In contrast, agmatine at a dose of 50mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although a reduction in the ED50 value of the antiepileptic drug from 517.5 to 629.1mg/kg was documented. Moreover, agmatine at doses of 50 and 100mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole-induced seizures in mice.In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings.

Indapamide enhances the protective action of carbamazepine, phenobarbital, and valproate against maximal electroshock-induced seizures in mice

To determine the influence of indapamide on the protective action of numerous conventional and second-generation antiepileptic drugs (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, topiramate and valproate) in the mouse maximal electroshock seizure model. Electroconvulsions were evoked in Albino Swiss mice by a current (sine-wave, 0.2 s stimulus duration) delivered via auricular electrodes. Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Indapamide (up to 3 mg/kg, i.p., 120 min before the test) neither altered the threshold for maximal electroconvulsions, nor protected the animals against maximal electroshock-induced seizures in mice. Moreover, indapamide (3 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenobarbital and valproate, but not that of lamotrigine, oxcarbazepine or topiramate in the maximal electroshock seizure test in mice. Indapamide (1.5 mg/kg) had no impact on the anticonvulsant action of all studied antiepileptic drugs in the maximal electroshock seizure test in mice. Estimation of total brain antiepileptic drug concentrations revealed that the observed interaction between indapamide and phenobarbital was complicated by a significant pharmacokinetic increase in total brain concentrations of phenobarbital. In contrast, indapamide had no impact on the total brain concentrations of carbamazepine and valproate in mice. The selective potentiation of the anticonvulsant action of carbamazepine and valproate by indapamide and lack of any pharmacokinetic interactions between drugs, make the combinations of indapamide with carbamazepine or valproate of pivotal importance for epileptic patients taking these drugs together.

Pharmacotherapy of Epilepsy: Focus on Levetiracetam

Levetiracetam is a second-generation antiepileptic drug which first came to the United States market in 1999. It has a mechanism of action that is not well elucidated. However, it is a very favorable antiepileptic drug due to its reliable pharmacokinetics, minimal drug interactions, seizure efficacy and good tolerability. It is an agent that has established efficacy as an adjunct therapy agent for partial and refractory seizures. As a monotherapy agent, levetiracetam also appears to be an attractive agent with observed efficacy and tolerability. Since levetiracetam has recently become available intravenously, it is also being reviewed as an agent for acute status epilepticus. In pediatrics, levetiracetam is widely used with efficacy seen in small clinical trials for a variety of seizure types. Levetiracetam is well tolerated: the most common adverse effect being somnolence and behavioral effects. Overall, levetiracetam is a notable antiepileptic drug that has added significantly to the current antiepileptic armamentarium.

Clinical Perspectives on Lacosamide

Despite the advent of new antiepileptic drugs (AEDs) over the past 15 years, the treatment of uncontrolled partial-onset seizures remains a dilemma for clinicians. The most recent AEDs offer new mechanisms of action and more favorable safety profiles than the first generation of AEDs. Lacosamide (LCM) is the latest AED awaiting approval by the FDA for adjunctive use in partial-onset seizures. It differs from all other approved AEDs in that it has two novel mechanisms of action and favorable pharmacokinetic and safety profiles. The purposes of this article are to present the significant parameters for its use in clinical practice, by summarizing the preliminary results of phase II and III clinical trials, and to compare its efficacy data with other second-generation AEDs.

Optimal Prevention of Seizures Induced by High‐Dose Busulfan

High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.

Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED(50) values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.

Treatment options for pregnant women with epilepsy

Background: Antiepileptic drugs (AEDs) in pregnancy are associated with an increased risk of fetal malformations. Concern is expressed about the effects that AEDs may produce on the child's cognition and development. To date, no specific malformations have clearly been proven to be attributable to a specific drug, with the exception of valproate. Objective: In order to gain prospective data, collaborative pregnancy registers have been established which collect data on teratogenicity and seizure control efficacy of AEDs, and on the comparative efficacy of second-generation AEDs. Methods: Studies of the effects of AED exposure on cognitive function have begun. Future head-to-head studies of traditional and newly developed AEDs may provide a more rational basis for defining first and second line choices of medications for women with epilepsy generally, and more specifically in pregnancy. Conclusions: Traditional prescribing patterns appear to influence the options for treatment of women with epilepsy in pregnancy, which is then adjusted according to the variability of response.

Guidance for off-label use of drugs

Guidance for off-label use of drugs

Use of Second-Generation Antiepileptic Drugs in the Pediatric Population

Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use. Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.

Economic Analysis of Newer Antiepileptic Drugs

In the last 20 years, several second-generation antiepileptic drugs (AEDs) have been marketed. These newer drugs are expensive and have no established superiority over the first-generation compounds in terms of efficacy when used as monotherapy. A systematic review of economic studies dealing with the newer AEDs has been performed to put these drugs in a wider perspective. A number of economic analysis studies of second-generation AEDs have examined these compounds as monotherapy or adjunctive therapy. Almost all monotherapy studies showed newer AEDs as having similar effectiveness but significantly higher acquisition costs than first-generation drugs. The evidence from adjunctive therapy studies was more conflicting. Lamotrigine appeared to be a cost-effective drug when higher thresholds were used, or when savings were defined by the cost of surgery. Levetiracetam also appeared to be cost effective when the costs of surgical investigation were discounted.In a decision model that included quantification of the uncertainty associated with the decision regarding the cost effectiveness of AEDs, second-generation drugs used as monotherapy for newly diagnosed partial epilepsy produced similar benefits but were more expensive than older drugs. The newer AEDs were more effective but more expensive than existing monotherapies in patients with refractory partial epilepsy, but may be cost effective at higher thresholds, and continue to be cost effective in patients responding to the assigned drug. In patients with newly diagnosed generalized epilepsy, valproate was more cost effective than lamotrigine.The results of current economic studies are difficult to assess and compare because of a number of methodological drawbacks. Future studies should be implemented using a standardized approach to define the costs and outcomes of representative cohorts of patients with newly diagnosed epilepsy recruited from different countries and followed prospectively.

Influence of aminophylline on the anticonvulsive action of gabapentin in the mouse maximal electroshock seizure threshold model

Accumulating evidence indicates that aminophylline [theophylline(2) x ethylenediamine] markedly attenuates the anticonvulsant action of conventional antiepileptic drugs in experimental animal models of epilepsy and evokes severe seizure activity in patients treated with this methylxanthine. The objective of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline on the anticonvulsant potential of gabapentin (a second-generation antiepileptic drug) in the mouse maximal electroshock seizure threshold model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of gabapentin in terms of motor coordination impairment were assessed in the chimney test. To evaluate pharmacokinetic characteristics of interaction between drugs, total brain concentrations of gabapentin and theophylline were estimated with high-pressure liquid chromatography and fluorescence polarization immunoassay, respectively. Results indicated that gabapentin (at doses of 75 and 100 mg/kg, i.p.) increased the threshold for electroconvulsions in mice. Aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, did not attenuate the anticonvulsant potential of gabapentin in the maximal electroshock seizure threshold test in mice. Similarly, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of gabapentin in the chimney test. Pharmacokinetic evaluation of total brain concentrations of gabapentin and theophylline revealed no significant changes in total brain concentrations of the drugs after both, acute and chronic applications of aminophylline in combination with gabapentin. The data show that aminophylline did not alter the ability of gabapentin to protect mice against seizures induced by electroconvulsive shock. The observed interaction between gabapentin and aminophylline in both acute and chronic experiments was pharmacodynamic in nature.

A New Look at the Second-Generation Antiepileptic Drugs

To review data from the literature regarding the efficacy and tolerability of the second-generation antiepileptic drugs which were approved by the Food and Drug Administration (FDA) since 1994. A MEDLINE search of the literature, as well as review of bibliographies, was performed to identify randomized controlled trials and other reports evaluating efficacy, pharmacokinetic profile, adverse effects, and drug interactions of the second-generation antiepileptic drugs. Key search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Each of the second-generation antiepileptic drugs has demonstrated statistically significant reductions in seizure frequency over baseline compared with placebo or active control. Limited studies of efficacy of the new agents compared with the traditional antiepileptic drugs found no significant differences. Each of the second-generation antiepileptic drugs has a unique pharmacokinetic and side-effect profile. Compared with the traditional agents, the second-generation antiepileptic drugs have fewer serious adverse effects, as well as drug interactions. Knowledge of the second-generation antiepileptic drugs has greatly expanded over the past decade. The newer agents offer many options in the treatment of epilepsy that are safe, efficacious, and well tolerated.

Isobolographic analysis of interaction between drugs with nonparallel dose–response relationship curves: a practical application

The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.

Second-Generation Antiepileptic Drugs' Impact on Balance: A Meta-analysis

OBJECTIVE To systematically review available evidence regarding whether second-generation antiepileptic drugs (AEDs) contribute to the risk of balance disorders. METHODS We systematically evaluated data from randomized controlled trials that compared adjunctive therapy with a second-generation AED (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, or zonisamide) vs placebo for partial epilepsy and that reported dose-specific rates of ataxia or imbalance for each group. Random-effects meta-analysis was used to pool ratios (risk ratio [RR]) and associated 95% confidence intervals to determine whether there was evidence of an overall AED class effect or a dose-response effect and whether there were differences between individual AEDs. RESULTS Sixteen studies met inclusion criteria, representing 4279 individuals randomized to a second-generation AED and 1830 patients to placebo. Pooled analyses of all AEDs demonstrated that they increase imbalance risk at any dose (RR, 2.73; 95% confidence interval, 2.07-3.61) and at lowest dose (RR, 1.76; 95% confidence interval, 1.26-2.46). The highest dose analysis showed heterogeneity; evaluation of individual AEDs revealed that oxcarbamazepine and topiramate increased imbalance risk at all doses, whereas gabapentin and levetiracetam did not increase imbalance risk at any dose. A dose-response effect was observed for most AEDs. CONCLUSION Second-generation AEDs at standard dosages, except for gabapentin and levetiracetam, increase the imbalance risk, and evidence exists for a dose-response effect. The mechanisms, risk factors, and consequences of this risk for individual AEDs warrant further study. To systematically review available evidence regarding whether second-generation antiepileptic drugs (AEDs) contribute to the risk of balance disorders. We systematically evaluated data from randomized controlled trials that compared adjunctive therapy with a second-generation AED (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, or zonisamide) vs placebo for partial epilepsy and that reported dose-specific rates of ataxia or imbalance for each group. Random-effects meta-analysis was used to pool ratios (risk ratio [RR]) and associated 95% confidence intervals to determine whether there was evidence of an overall AED class effect or a dose-response effect and whether there were differences between individual AEDs. Sixteen studies met inclusion criteria, representing 4279 individuals randomized to a second-generation AED and 1830 patients to placebo. Pooled analyses of all AEDs demonstrated that they increase imbalance risk at any dose (RR, 2.73; 95% confidence interval, 2.07-3.61) and at lowest dose (RR, 1.76; 95% confidence interval, 1.26-2.46). The highest dose analysis showed heterogeneity; evaluation of individual AEDs revealed that oxcarbamazepine and topiramate increased imbalance risk at all doses, whereas gabapentin and levetiracetam did not increase imbalance risk at any dose. A dose-response effect was observed for most AEDs. Second-generation AEDs at standard dosages, except for gabapentin and levetiracetam, increase the imbalance risk, and evidence exists for a dose-response effect. The mechanisms, risk factors, and consequences of this risk for individual AEDs warrant further study.

Second-Generation Antiepileptic Drugs' Impact on Balance: A Meta-analysis

To systematically review available evidence regarding whether second-generation antiepileptic drugs (AEDs) contribute to the risk of balance disorders. We systematically evaluated data from randomized controlled trials that compared adjunctive therapy with a second-generation AED (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topIramate, or zonisamide) vs placebo for partial epilepsy and that reported dose-specific rates of ataxia or Imbalance for each group. Random-effects meta-analysis was used to pool ratios (risk ratio [RR]) and associated 95% confidence Intervals to determine whether there was evidence of an overall AED class effect or a dose-response effect and whether there were differences between Individual AEDs. Sixteen studies met inclusion criteria, representing 4279 individuals randomized to a second-generation AED and 1830 patients to placebo. Pooled analyses of all AEDs demonstrated that they Increase imbalance risk at any dose (RR, 2.73; 95% confidence interval, 2.07-3.61) and at lowest dose (RR, 1.76; 95% confidence interval, 1.26-2.46). The highest dose analysis showed heterogeneity; evaluation of individual AEDs revealed that oxcarbamazepine and topiramate increased imbalance risk at all doses, whereas gabapentin and levetiracetam did not increase imbalance risk at any dose. A dose-response effect was observed for most AEDs. Second-generation AEDs at standard dosages, except for gabapentin and levetiracetam, increase the imbalance risk, and evidence exists for a dose-response effect. The mechanisms, risk factors, and consequences of this risk for individual AEDs warrant further study.