The New Antiepileptic Drugs: A Systematic Review of Their Efficacy and Tolerability

: Purpose: Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as “add-on” treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability. Methods: Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a 350% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIS; 50% responders) or 99% CIS; side effects) were calculated. Results: Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53–3.43); LTG, 2.32 (1.47–3.68); TGB, 3.03 (2.01–4.58); TPM, 4.07 (2.87–5.78); VGB, 3.67 (2.44–5.51); and ZNS, 2.7 (1.36–4.47). ORs for discontinuation were GBP, 1.36 (0.75–2.49); LTG, 1.19 (0.79–1.79); TGB, 1.81 (1.21–2.70); TPM, 2.56 (1.64–4.00); VGB, 2.58 (126–5.27); and ZNS, 4.23 (1.71–10.49). Conclusions: We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.     

The New Antiepileptic Drugs and Women: Efficacy, Reproductive Health, Pregnancy, and Fetal Outcome

Summary: As new antiepileptic drugs (AEDs) become available, physicians will define their appropriate use in particular patient populations. For women, the issues in clude gender-specific efficacy and tolerability, including the impact of the AED on reproductive health. Women with epilepsy who are treated with established AEDs ap pear to be at risk for compromised bone health, for dis turbances in fertility, menstrual cyclicity, ovulatory func tion, and sexuality and, with some AEDs, for failure of hormonal contraception. Finally, pregnancy outcome may be adversely affected by the established AEDs, all of which are human teratogens. Felbamate (FBM), gabap-entin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were reviewed. The preclinical development pro cess had not addressed all the issues of concern to women. Although gender-specific efficacy is routinely evaluated, impact on reproductive health is not. FBM, GBP, LTG, TGB, TPM, and VGB have similar efficacy in women and men. It is not known whether the new AEDs will affect bone health, fertility, the menstrual cycle, and sexuality. FBM, GBP, LTG, TGB, and probably VGB do not interfere with hormonal contraception. Whether these new AEDs are good choices for the pregnant woman with epilepsy awaits further experience in human pregnancy. However, animal reproductive toxicology studies appear promising. The limited number of human pregnancy ex posures do not, thus far, signal a significant number or particular type of adverse outcomes. However, only with improved postmarketing surveillance can essential infor mation about teratogenic effects be acquired in an accept ably short time.     

Interaction between anticonvulsants and human placental carnitine transporter

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.     

Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.     

Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy

To characterize the type of interactions between vigabatrin (VGB) and tiagabine (TGB) -- two newer antiepileptic drugs influencing GABA-ergic neurotransmitter system, the isobolographic analysis was used in two experimental models of epilepsy: the maximal electroshock seizure threshold (MEST) test and pentylenetetrazole (PTZ)-induced seizures in mice. Results indicated that VGB and TGB administered separately (i.p.) increased the electroconvulsive threshold in mice, which allowed the calculation of their TID(20) values (threshold increasing doses by 20% over the threshold of control animals) in the MEST test. The TID(20) for VGB was 226.2 mg/kg and that for TGB was 4.4 mg/kg. With isobolography, the combinations of VGB with TGB (at fixed-ratios of 1:3, 1:1 and 3:1) exerted additive interactions in the MEST test in mice. Similarly, VGB and TGB injected separately (i.p.) suppressed the PTZ-induced seizures, and their ED(50) values (median effective doses, protecting 50% of the animals tested against clonic convulsions) for VGB and TGB were 622.5 mg/kg and 0.8 mg/kg, respectively. Isobolographic analysis of interactions revealed that the combinations of VGB with TGB at the fixed-ratios of 1:3 and 1:1 produced supra-additive (synergistic) interactions against PTZ-induced seizures. Only the combination of VGB with TGB at the fixed-ratio of 3:1 was additive in the PTZ test. The evaluation of acute adverse-effect potential for all fixed-ratio combinations of VGB with TGB (administered at their TID(20) and ED(50) values from the MEST and PTZ tests) revealed that none of the examined combinations affected motor coordination in the chimney test and altered neuromuscular tone in the grip-strength test in mice. In contrast, VGB in combinations with TGB produced the antinociceptive effects with respect to suppression of acute thermal pain in animals subjected to the hot-plate test. Based on this preclinical study, one can ascertain that the combination of VGB with TGB would provide an adequate seizure control in epileptic patients.     

The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.

PURPOSE: Lamotrigine (LTG), vigabatrin (VGB) and gabapentin (GBP) are three anti-epileptic drugs (AEDs) used in the treatment of children with epilepsy for which long-term retention rates are not currently well known. This study examines the efficacy, long-term survival and adverse event profile of these three agents used as add-on therapy in children with refractory epilepsy over a 10-year period. METHODS: Three separate audits were conducted between February 1996 and September 2000. All children studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure free or achieved >50% reduction in seizure frequency for 6 months or more after starting therapy. Adverse events and patient survival for each drug were recorded at the end of the study period. RESULTS: Between September 1990 and February 1996, 132 children received LTG, 80 VGB and 39 GBP. At the 10-year follow-up audit, 33% of the children on LTG had a sustained beneficial effect on their seizure frequency in contrast to 19% for VGB and 15% for GBP. No significant difference in efficacy was found in children with partial seizures. Children with epileptic encephalopathy (EE) including myoclonic-astatic epilepsy and Lennox-Gastaut Syndrome (LGS) achieved a more favorable response to LTG. The main reasons for drug withdrawal were lack of efficacy for VGB, apparent worsening of seizures for GBP and the development of a rash for LTG. CONCLUSIONS: Lamotrigine is a useful add-on therapy in treating children with epilepsy. It has a low adverse event profile and a sustained beneficial effect in children with intractable epilepsy.     

Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long‐term studies?

OBJECTIVE: A review of long-term open-label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs). METHODS: From more than 500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year. RESULTS: No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty-two studies reported the number of patients withdrawing due to adverse effects. LEV was the best-tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40-60% and LEV had a retention rate of 60-75%. CONCLUSION: One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation.

PURPOSE: the choices available for patients whose partial seizures are poorly controlled include seven new antiepileptic drugs (AEDs) or vagal nerve stimulation (VNS) as add-on therapy. Comparisons are needed to help physicians and patients select among the options for treatment. METHODS: we compared efficacy and adverse events of new treatments from controlled clinical trials of patients with uncontrolled partial seizures. Response rates (> or =50% decrease in partial seizures) at doses recommended in product labeling for adjunct therapy were tabulated for overall success (placebo response rate subtracted from AED response rate). Adverse events listed in product labeling were tabulated as complaint rates (placebo events subtracted from AED events). VNS trials used low dose stimulation as a pseudo-placebo. RESULTS: overall success rates fell into two general groups with ranges of 12-20% for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), zonisamide and 27-29% for levetiracetam, oxcarbazepine, and topiramate (TPM). Summary Complaint Scores also fell into two general groups with ranges of -27 to -82 for GBP, levetiracetam, TGB, zonisamide and -113 to -205 for LTG, oxcarbazepine and TPM. VNS scores were in the lower or higher success and summary complaint categories depending on whether scores from the pseudo-placebo group were subtracted from the high dose group. CONCLUSIONS: these data allow comparisons among AEDs and VNS using similar data from standard types of clinical trials.     

Overview of the Safety of Newer Antiepileptic Drugs

Summary: Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.     

The Long-Term Use of Gabapentin, Lamotrigine, and Vigabatrin in Patients with Chronic Epilepsy

PURPOSE: To compare the long-term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure-related injury/hospital admission and mortality after these drugs were commenced. METHODS: This was a retrospective case-records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan-Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure-related injury/hospital admissions and standardised mortality ratios were calculated. RESULTS: There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was <40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure-related injury/admission. CONCLUSIONS: The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.     

Sildenafil influences the anticonvulsant activity of vigabatrin and gabapentin in the timed pentylenetetrazole infusion test in mice

Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to affect convulsant activity in some animal models of seizures and epilepsy. Moreover, its influence on the protective activity of some antiepileptic drugs (AEDs) was also noted. The aim of the present study was to investigate the effect of sildenafil on the anticonvulsant potential of gabapentin (GBP) and vigabatrin (VGB) in the timed intravenous (i.v.) pentylenetetrazole (PTZ) test in mice. The chimney test, the passive avoidance task and the grip strength test were used to estimate some possible side effects caused by the studied AEDs and their combinations with sildenafil. Total brain and free plasma concentrations of GBP and VGB were determined to evaluate the characteristics of interactions. Our studies revealed that GBP (25-100mg/kg) increases the threshold for the forelimb tonic extension, whereas VGB raises thresholds both, for myoclonic (200-600mg/kg) and generalized clonic (400-600mg/kg) seizures in the used model of seizures. GBP at sub-effective dose of 12.5mg/kg co-administered with sildenafil at doses of 10 and 20mg/kg significantly increases the threshold for tonic seizures in the i.v. PTZ test in mice. Combination of sub-effective dose of VGB (200mg/kg) with sildenafil at a dose of 5mg/kg also showed significant anticonvulsant activity against clonic seizures. The studied AEDs and their combinations with sildenafil did not produce any changes in the motor coordination, long-term memory and muscular strength in mice. Sildenafil did not influence total brain and free plasma concentrations of GBP and VGB. Interactions between the studied AEDs and sildenafil were pharmacodynamic in nature and for that reason they are worthy of consideration in the clinical practice.     

Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

Characteristics of patients initiated on the new antiepileptic drugs: a PADS study

Whereas randomized controlled trials remain a standard for evaluating and comparing efficacy and safety of the new antiepileptic drugs (AEDs), postmarketing drug research offers a useful means of comparing efficacy and safety of new AEDs. However, differences in baseline characteristics of patients in different drug groups create the potential for bias in drug comparison studies. In this study, baseline demographic characteristics of 1,386 patients initiating lamotrigine (LTG), tiagabine (TGB), or topiramate (TPM) were compared to identify patient characteristics that may influence AED use in epilepsy patients. Data were collected at 14 epilepsy centers and included medications, seizure types and syndromes, and prior adverse events. There were 402 patients in the LTG group, 725 TPM, and 259 TGB. The groups differed both in their number of concurrent AEDs (p<0.001) and in their number of prior AEDs (p<0.01). There was no difference in proportion with partial versus generalized epilepsy syndromes. The groups differed in the proportions of patients with complex partial seizures (p=0.049), primary generalized tonic-clonic seizures (p=0.01), and myoclonic seizures (p=0.03). Baseline behavioral adverse event rate was lowest in patients initiating TPM (p<0.01); LTG patients had the lowest rate of prior AED-related rash (p=0.02). There was no relationship between AED assignment and patient age, age of epilepsy onset, epilepsy duration, institutionalization status, gender, or psychiatric history. Numerous epidemiological differences were identified among patients placed on the new AEDs, including current and prior AED profiles, seizure types, and prior adverse event history. Accounting for these differences is of crucial importance because they may bias conclusions of nonrandomized post-marketing trials comparing the drugs.     

Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy

PURPOSE: We sought to determine the long-term retention rates of lamotrigine (LTG), gabapentin (GBP), and topiramate (TPM) therapy for patients at a tertiary referral clinic for chronic, refractory epilepsy. METHODS: We analyzed 424 consecutive patients with chronic, refractory partial and/or generalized epilepsy who were started on LTG, 158 patients who were started on GBP, and 393 patients who were started on TPM. The percentages of patients who continued therapy with LTG, GBP, and TPM were estimated with the use of Kaplan-Meier survival analysis. Factors that influence retention were analyzed with the use of Cox regression analysis. RESULTS: Kaplan-Meier survival analysis showed that at 3 years, 30% continued therapy on TPM compared with 29% on LTG and fewer than 10% on GBP. Adverse events resulted in therapy withdrawal in 40% of patients on TPM compared with GBP (37%) and LTG (22%). Perceived lack of efficacy led to treatment withdrawal in 39% of patients on GBP compared with 34% on LTG and 19% on TPM. Cox regression estimated that a fourth or fewer of patients with chronic partial epilepsy are likely to continue therapy with a new antiepileptic drug beyond 5 years. CONCLUSIONS: The impact of these new antiepileptic drugs on the long-term course of chronic partial epilepsy is likely to be small, as approximately three of four patients will discontinue therapy. More patients appear to continue on TPM compared with LTG or GBP, with a possible reason being better perceived efficacy of TPM, despite having the highest incidence of adverse events.     

Lamictal (Lamotrigine) Monotherapy for Typical Absence Seizures in Children

PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.     

Expanding Antiepileptic Drug Options: Clinical Efficacy of New Therapeutic Agents

Summary: Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM), lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were reviewed. In three European multicenter studies of TPM, the clinical efficacy of 400–, 600–, and 800-mg/day target dosages was demonstrated. In a similarly designed United States trial, LTG was significantly superior to placebo at a 500-mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of smaller trials of VGB suggests that a ≥50% reduction in seizures is observed in approximately 45% of patients with refractory partial epilepsy. All of these newer antiepileptic drugs have shown efficacy in well-controlled trials and should contribute significantly to our ability to manage partial epilepsy.     

Effect of antiepileptic drugs on spontaneous seizures in epileptic rats

The present study investigated whether spontaneously seizing animals are a valid model for evaluating antiepileptic compounds in the treatment of human epilepsy. We examined whether clinically effective antiepileptic drugs (AEDs), including carbamazepine (CBZ), valproic acid (VPA), ethosuximide (ESM), lamotrigine (LTG), or vigabatrin (VGB) suppress spontaneous seizures in a rat model of human temporal lobe epilepsy, in which epilepsy is triggered by status epilepticus induced by electrical stimulation of the amygdala. Eight adult male rats with newly diagnosed epilepsy and focal onset seizures were included in the study. Baseline seizure frequency was determined by continuous video-electroencephalography (EEG) monitoring during a 7 days baseline period. This was followed by a 2-3 days titration period, a 5-7 days treatment period, and a 2-3 days wash-out period. During the 5-7 days treatment period, animals were treated successively with CBZ (120 mg/kg/day), VPA (600 mg/kg/day), ESM (400 mg/kg/day), LTG (20 mg/kg/day), and VGB (250 mg/kg/day). VPA, LTG, and VGB were the most efficient of the compounds investigated, decreasing the mean seizure frequency by 83, 84, and 60%, respectively. In the VPA group, the percentage of rats with a greater than 50% decrease in seizure frequency was 100%, in the LTG group 88%, in the VGB group 83%, in the CBZ group 29%, and in the ESM group 38%. During the 7 day treatment period, 20% of the VPA-treated animals and 14% of the CBZ-treated animals became seizure-free. These findings indicate that rats with focal onset spontaneous seizures respond to the same AEDs as patients with focal onset seizures. Like in humans, the response to AEDs can vary substantially between animals. These observations support the idea that spontaneously seizing animals are a useful tool for testing novel compounds for the treatment of human epilepsy.