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Objective: We assessed the efficacy and safety of once-daily eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients., Methods: This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: eslicarbazepine acetate 800 mg/carbamazepine-CR 200 mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: eslicarbazepine acetate 1200 mg/carbamazepine-CR 400 mg BID, level C: eslicarbazepine acetate 1600 mg/carbamazepine-CR 600 mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6 months after stabilization in the per protocol set. The predefined noninferiority criteria were -12% absolute and -20% relative difference between treatment groups., Results: Eight hundred fifteen patients were randomly assigned; 785 (388 in the eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6 months at the last evaluated dose (average risk difference = -4.28%, 95% confidence interval [CI] = -10.30 to 1.74; relative risk difference = -5.87%, 95% CI = -13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = -3.07, 95% CI = -9.04 to 2.89)., Significance: Treatment with eslicarbazepine acetate was noninferior to BID carbamazepine-CR. With its once-daily formulation, eslicarbazepine acetate provides a useful option for first-line monotherapy for adults with newly diagnosed epilepsy and focal onset seizures., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL)., Methods: Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule., Results: 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD., Conclusions: Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Pooled evaluation of the key efficacy and safety profile of eslicarbazepine acetate (ESL) added-on to stable antiepileptic therapy in adults with focal-onset seizures., Methods: Data from 1703 patients enrolled in four phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2 week titration period, ESL was administered at 400 mg, 800 mg, and 1200 mg once-daily doses for 12 weeks (maintenance period). Pooled efficacy variable was standardized (/4 weeks) seizure frequency (SSF) analyzed over the maintenance period as reduction in absolute and relative SSF and proportion of responders (≥50% reduction in SSF). Pooled safety was analyzed by means of adverse events and clinical laboratory assessments., Results: SSF was significantly reduced with ESL 800 mg (P < 0.0001) and 1200 mg (P < 0.0001) compared to placebo. Median relative reduction in SSF was 33.4% for ESL 800 mg and 37.8% for 1200 mg (placebo: 17.6%), and responder rate was 33.8% and 43.1% (placebo: 22.2%). ESL was more efficacious than placebo regardless of gender, geographical region, epilepsy duration, age at time of diagnosis, seizure type, and type of concomitant antiepileptic drugs (AED). Incidence of adverse events (AEs) and AEs leading to discontinuation was dose dependent. Most common AEs (>10% patients) were dizziness, somnolence, and nausea. The incidence of treatment-emergent AEs (dizziness, somnolence, ataxia, vomiting, and nausea) was lower in patients who began taking ESL 400 mg (followed by 400 mg increments to 800 or 1200 mg) than in those who began taking ESL 600 mg or 800 mg., Conclusions: Once-daily ESL 800 mg and 1200 mg showed consistent results across all efficacy and safety endpoints, independent of study population characteristics and type of concomitant AEDs. Treatment initiated with ESL 400 mg followed by 400 mg increments to 800 or 1200 mg provides optimal balance of efficacy and tolerability., (© 2017 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones., Methods: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls., Results: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 μmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three., Conclusions: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy., Methods: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012., Results: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years., Conclusions: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers., Methods: Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers., Key Findings: Mean eslicarbazepine Cmax,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively., Significance: ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss ) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Background: Antiepileptic drugs (AEDs) are commonly used in the treatment of epilepsy, psychiatric diseases and pain disorders. Several of these drugs influence blood levels of folate and vitamin B12 and, consequently, homocysteine. This may be relevant for AED effects and side effects. However, not only folate and vitamin B12, but also genetic variants modify homocysteine metabolism. Here, we aimed to determine whether there is a pharmacogenetic interaction between folate, vitamin B12 and genetic variants and homocysteine plasma level in AED-treated patients., Methods: In this mono-center study, we measured homocysteine, folate and vitamin B12 plasma levels in a population of 498 AED-treated adult patients with epilepsy. In addition, we analyzed the genotypes of seven common genetic variants of homocysteine metabolism: methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C, methionine synthase (MTR) c.2756A>G, dihydrofolate reductase (DHFR) c.594+59del19bp, cystathionine β-synthase (CBS) c.844&#95;855ins68, transcobalamin 2 (TC2) c.776C>G and methionine synthase reductase (MTRR) c.66G>A., Results: On multivariate logistic regression, folate and vitamin B12 levels, but none of the genetic variants, were predictive for homocysteine levels., Conclusions: These data suggest that, in AED-treated patients, folate and vitamin B12 play important roles in the development of hyperhomocysteinemia, whereas genetic variants of homocysteine metabolism do not and thus do not contribute to the risk of developing hyperhomocysteinemia during AED treatment.

Purpose: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures., Methods: Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks., Key Findings: Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations., Significance: Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Background and Purpose: Treatment with topiramate (TPM) is known to negatively affect executive functions and verbal fluency in particular. However, judgments of cognitive side effects under TPM rarely consider clinical conditions and possible effects of epilepsy, treatment, and drug load., Methods: This retrospective cross-sectional study in large cohorts of patients with epilepsy evaluated the impact of TPM mono- and polytherapy on verbal fluency. To isolate TPM-induced effects from those of epilepsy and antiepileptic medication in general, verbal fluency under TPM (N = 421) was compared to the performance of a matched sample of patients with an antiepileptic medication other than TPM (N = 351), untreated patients (N = 108), and healthy controls (N = 100)., Results: Impaired verbal fluency performance was seen in 77% of the patients treated with TPM. Compared to healthy controls, verbal fluency in untreated patients was reduced by 22%, under monotherapy without TPM by 31% and under TPM monotherapy by 45%. With and without TPM, verbal fluency performance linearly decreased with each additional drug in polytherapy. On each level, performance under TPM was 21-28% worse than in the respective condition without TPM. Unimpaired performance under TPM was primarily associated with lower dose, higher education, and a later onset of epilepsy., Conclusions: The majority of patients under TPM shows reduced verbal fluency. However, when taking the cumulative negative effects of epilepsy, and the concomitant drug regimen into account, TPM is associated with a 21-28% poorer performance as compared with other drugs. Additionally, the data indicate an impact of dose and reserve capacity on the occurrence of impairments., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Objective: To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs)., Methods: Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry., Results: Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0μg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0-24)) were 132.5, 205.4 and 336.1μgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites., Conclusions: Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures., Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (≥50% reduction in baseline seizure frequency) were assessed., Results: The intention-to-treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)-treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG)-treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%)., Conclusions: In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures., Classification of Evidence: This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures.

Purpose: To evaluate the long-term efficacy and safety of once daily eslicarbazepine acetate (ESL) as adjunctive therapy for partial-onset seizures in adults with epilepsy., Methods: One-year open-label treatment extension with ESL in patients who completed a placebo-controlled pivotal study (Epilepsia 2009; 50: 454-463). Starting dose was 800 mg once daily, for 4 weeks; thereafter, dose could be titrated up or down. Doses of concomitant antiepileptic drugs were to be kept stable., Results: Overall, 314 patients were enrolled. The intent-to-treat population consisted of 312 patients, and 239 (76.6%) completed 1 year of treatment. ESL median dose was 800 mg once daily. Compared to baseline, median seizure frequency decreased by 39% during the first 4 weeks and between 48% and 56% thereafter. The responder rate (≥50% seizure reduction) was 41% during weeks 1-4 and, thereafter ranged between 48% and 53%. The proportion of seizure-free patients per 12-week interval ranged between 8.7% and 12.5%. Quality of life, as measured by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), and depressive symptoms, as measured by the Montgomery Asberg Depression Rating Scale (MADRS), improved significantly compared to baseline. Treatment-emergent adverse events (TEAEs) were reported by 51% of patients. The most frequent TEAEs were headache (10%), dizziness (10%), diplopia (5%), and nasopharyngitis (5%). TEAEs were mostly (97%) of mild to moderate intensity. Eleven patients (3.5%) discontinued due to TEAEs. There were no results of laboratory tests raising safety concerns., Discussion: Sustained therapeutic effect, favorable tolerability and safety, and an improvement in quality of life and depressive symptoms were observed during long-term add-on treatment of partial-onset seizures in adults with once daily ESL., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Purpose: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with >or=4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1-2 antiepileptic drugs (AEDs)., Methods: This multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks)., Results: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log-transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56-62% of patients), lamotrigine (25-27%), and valproic acid (22-28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate., Discussion: ESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.

Objectives: The goals of this study were to observe behavioral changes in patients receiving levetiracetam (LEV), a newer antiepileptic drug (AED), and to answer the question of whether LEV exerts a specific effect on impulse control and aggression., Methods: We asked 288 consecutive patients with epilepsy on LEV (90% polytherapy, mean dose=2689 mg) and 135 relatives whether LEV caused a positive or negative behavioral change. Forty-three patients on other AEDs served as a control group. Ratings were related to patient characteristics, efficacy, dose, drug load, bidirectional ratings of change in behavioral domains, and questionnaires on personality (Fragebogens zur Persönlichkeit bei zerebralen Erkrankungen) and impulsivity (Barratt Impulsiveness Scale-11)., Results: LEV was rated as very effective by 40% of the patients. In contrast to only 9% of the controls, a considerable number of patients reported a behavioral change while taking LEV (12% very negative, 25% negative, 16% positive, 6% very positive). Negative ratings were due to loss of self-control, restlessness, sleep problems, and, most importantly, aggression. Positive ratings were due to increased energy, vigilance, and activation. Increases in psychomotor speed, concentration, and remote memory indicated subjectively experienced positive effects on cognition. The proxy reports indicated reliable self-reports. Reported change was not related to type of epilepsy, co-therapy, dose, drug load, or psychiatric history. Negative effects were, however, associated with poorer seizure control, mental retardation, indicators of an organic psychosyndrome, and nonplanning impulsiveness., Conclusion: The results indicate that LEV exerts a dose-independent stimulating effect that can be positive or negative. Aggression is a prominent feature. Lack of efficacy, mental retardation, and presumably also pre-intake disposition (organic psychosyndrome, impulsivity) may be helpful in predicting whether additional activation under LEV will be positive or negative.

Objective: To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy., Methods: A multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18-65 years with >or=4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n=50), twice daily (BID, n=46), or placebo (PL, n=47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a >or=50% seizure reduction) was the primary end point., Results: The percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =-infinity, -14; p=0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =-infinity, -1; p=0.12). A significantly higher proportion of responders in weeks 5-8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p=0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred., Conclusion: Eslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients.

Objective: Whereas the efficacy of the newer antiepileptic drugs (AEDs) is well established, there remain questions regarding their cognitive side effects. Therefore, we performed a comparative open randomized trial with TPM and TGB as add-on therapy, with particular consideration of cognition, mood, and health-related quality of life (HRQOL)., Methods: Forty-one patients with refractory epilepsy were randomly assigned to one of the two treatment groups (TPM vs TGB) and received neuropsychological testing at baseline (T1), after titration (3 months, T2), and during the maintenance phase (another 3 months, T3). Tests included measures of intelligence, attention, working memory, episodic memory, language, and self-report questionnaires regarding mood and HRQOL. Twenty patients (8 TPM, 12 TGB) discontinued the trial for different reasons (no group difference)., Results: Seizure outcome (intention-to-treat analysis) was comparably good in both groups (8.1% seizure free, 29.7% seizure reduction>50%). From baseline to after the titration paired sample t tests revealed significant deterioration in verbal fluency, language comprehension, working memory, and visual block tapping under TPM and a deterioration in verbal memory (delayed free recall) in the TGB group. These functions remained stable in the maintenance phase. Self-report measures initially indicated concerns about AED side effects in both groups and concerns about worse cognitive functioning and depression under TPM. In the maintenance phase the TGB group reported feeling a lack of energy, whereas patients on TPM demonstrated improvement on all QOLIE scales on a descriptive level., Conclusion: This study demonstrates the comparable efficacy of TPM and TGB. Consistent with previous reports, TPM but not TGB appears to be associated with persistent negative cognitive side effects on frontal lobe-associated functions, the degree of which may be estimated by the fact that this effect was observed with a very small sample size. In contrast, in patients taking TPM, initially negatively affected HRQOL returns to baseline in the long run on a descriptive level. The latter finding may be interpreted in accordance with the observation that objective performance and subjective self-report under TPM can be dissociated.

Oxcarbazepine (OXC, trade names Timox, Trileptal is a new antiepileptic drug (AED) for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children older than 6 years of age. Although OXC was developed through structural variation of carbamazepine in order to avoid side effects from metabolites, significant differences have emerged between the two drugs. The mechanism of action mainly involves blockade of sodium currents but differs from CBZ by modulating different types of calcium channels. In contrast to CBZ, which is oxidized by the cytochrome P-450 system, OXC undergoes reductive metabolism at its ketomoiety to form MHD, which is glucuronidated and excreted in the urine. Involvement of the hepatic cytochrome P450-dependent enzymes in the metabolism of OXC is minimal. This allows for better combining of OXC with other AEDs such as valproate. In postmarketing experience of over 800,000 patient-years, OXC also showed an advantageous risk-benefit ratio. Oxcarbazepine should be preferred over CBZ and other older AEDs due to its very good efficacy and better side effect profile in children, adolescents, and adults with partial seizures.

Controlled clinical trials and routine clinical practice demon-strate that levetiracetam is effective as add-on therapy and appears to allow for withdrawal to monotherapy in patients who respond well in the add-on setting. In pivotal clinical trials of adjunctive therapy with levetiracetam 1000 to 3000 mg/day (pooled data), 40% to 54% of patients experienced a 50% or greater reduction in seizure frequency, compared with 18% to 28% of patients treated with placebo. The median percent reduction from baseline in seizure frequency ranged from 36% to 68% for levetiracetam, versus 10% to 23% for placebo. Seizure freedom was achieved by 11% to 35% of those in the levetiracetam treatment group, compared with 3% to 18% of those in the placebo group. (All comparisons statistically significant versus placebo for simple partial, complex partial, and secondarily generalized seizures except for percentage of seizure-free patients with simple partial seizures.) Clinical obser-vations are consistent with these findings.

Purpose: To evaluate the long-term impact of surgical treatment on seizure outcome and antiepileptic drug (AED) use in patients with pharmacoresistant temporal lobe epilepsy (TLE)., Methods: Comparison of seizure outcome and AED us in operated-on TLE patients (n=148) and nonsurgically treated TLE patients (n=94) at a baseline visit and a follow-up visit after a mean period of 4.8 years., Results: At follow-up, 44.6% of the surgical patients and 4.3% of the nonsurgical patients had been continuously seizure- free since the baseline visit (including the immediate postoperative period). A further 17.6% of the operated-on and 3.2% of the not operated-on patients had been seizure-free for at least the previous year; 37.8% of the surgical and 92.5% of the nonsurgical patients had had seizures during the previous 12 months (p < 0.001). Of the surgical patients, 8.8% versus none of the nonsurgical patients were AED free at follow-up; 55.4% versus 20.2% were receiving monotherapy, and 35.8% versus 79.8% were receiving polytherapy (p < 0.001). Mean number of AEDs and mean change in number of AEDs were significantly more favorable in operated-on than in non-operated-on patients. Further subgroup analysis revealed that not only the continuously seizure-free surgical patients, but also the operated-on patients with ongoing seizures took fewer AEDs than their respective non-operated-on counterparts., Conclusions: This controlled study for the first time provides comprehensive information on long-term seizure outcome and AED use in surgical TLE patients. It shows a more favorable seizure outcome and AED use in the surgically treated patients. The latter holds true even for the not seizure-free patient subgroup.

Unlabelled: Carbamazepine is a standard anticonvulsant in children and adults. Until now there is only little information available on its use in neonates. We investigated the oral administration of carbamazepine in refractory neonatal seizures treated with phenobarbital. Ten preterm infants (gestational age 23 + 6-34 + 6 weeks, birth weight 640 g-3080 g) with neonatal seizures were refractory to a primary therapy with phenobarbital. All patients subsequently received carbamazepine exclusively as a second choice anticonvulsant. A daily dose of 7-23 mg/kg carbamazepine was administered orally in two to three aliquots. All patients reached therapeutic plasma drug levels (3-12 mg/l; 13-50 mumol/l). In nine out of ten patients (complete group of small preterms with gestational age under 30 weeks and weight less than 1000 g), therapeutic success was excellent. Carbamazepine was continued for 1-5 months. After termination of therapy no further seizures occurred, also on EEG recordings. Finally, no carbamazepine-induced adverse effects were observed., Conclusion: This is the first report on the use of carbamazepine in small preterm infants. Carbamazepine may provide a useful and effective oral maintenance therapy in the management of neonatal seizures in these patients.

Objectives: To evaluate the efficacy and tolerability of losigamone (LSG)., Patients and Methods: Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo)., Results: The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients., Conclusions: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.

Purpose: The goal of the study was to evaluate the safety and efficacy of a broad oxcarbazepine (OXC) dosage range (600, 1200, and 2400 mg/d) as adjunctive therapy for uncontrolled partial seizures and to determine the relationship between trough plasma 10-monohydroxy derivative concentrations and OXC safety and efficacy., Methods: This multinational, multicenter, randomized, 28-week, double-blind, placebo-controlled, four-arm, parallel-group trial enrolled 694 patients aged 15-65 years with uncontrolled partial seizures with or without secondarily generalized seizures. The primary efficacy variable was percentage change in seizure frequency per 28 days relative to baseline., Results: The median reduction in seizure frequency was 26%, 40%, 50%, or 8% for patients receiving 600, 1200, or 2400 mg/d OXC or placebo, respectively (all p < or = 0.0001). Of patients in the 600, 1200, or 2400 mg/d OXC groups, 27%, 42%, and 50% respectively, had more than 50% reduction in seizure frequency compared with 13% for placebo (all p < 0.001). Higher plasma 10-monohydroxy derivative concentrations were associated with larger decreases in seizure frequency (p = 0.0001). During the double-blind treatment phase, 84%, 90%, 98%, and 76% of patients receiving 600, 1200, or 2400 mg/d OXC or placebo, respectively, reported one or more adverse events. The most common adverse events were related to the nervous and digestive systems., Conclusions: OXC is safe and effective as adjunctive therapy in patients with uncontrolled partial seizures. OXC 600 mg/d was the minimum effective dosage; effectiveness of OXC increased with dose. The rapid and fixed titration to high doses was associated with an increased risk of adverse events, which could potentially be reduced by adjusting concomitant antiepileptic medication and by using a slower, flexible OXC titration schedule.

Oxcarbazepin (OXC; 10,11-dihydro-10-oxo-5H-dibenz-[b,f]azepin-5-carboxamid, trade name Trileptal) is a new antiepileptic drug for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children above 6 years of age. It was developed through structural variation of carbamazepine. Extensive postmarketing use includes more than 200,000 patient years. The mechanism of action mainly involves blockage of sodium currents. The recommended daily starting dose of oxcarbazepin for both mono- and adjunctive treatment is 8-10 mg/kg (600 mg/day for adults) in two doses and can be titrated according to clinical benefit up to 2400 mg/day. Oxcarbazepin undergoes reductive metabolism at its keto moiety to form MHD, which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. Thus, OXC has limited drug interactions and does not require slow titration, allowing for better tolerability. Oxcarbazepin compares favorably to presently available new anticonvulsants of the second generation for two reasons: it is available immediately for both mono- and adjunctive therapy in adults and children, and extensive postmarketing experience from many countries is already available. In addition, OXC has been thoroughly tested in an unusually large clinical development program and been shown to be similarly effective as standard antiepileptic drugs.

Purpose: Metabotropic glutamate receptors (mGluRs) might be promising new drug targets for the treatment of epilepsy because the expression of certain mGluRs is regulated in epilepsy and because activation of mGluRs results in distinctive anti- and proconvulsant effects. Therefore, we examined how mGluR activation modulates high-voltage-activated (HVA) Ca2+ channels., Methods: Whole-cell patch-clamp recordings were obtained from granule cells and interneuron-like cells acutely isolated from the dentate gyrus of patients with pharmacoresistent temporal lobe epilepsy., Results: Agonists selective for either group I or group II mGluRs rapidly and reversibly reduced HVA currents in most dentate gyrus cells. These modulatory effects were inhibited by the respective group I and group II mGluR antagonists. The specific Ca2+ channel antagonists nifedipine and omega-conotoxin GVIA potently occluded the effects of group I and II mGluR agonists, respectively, indicating that group I mGluRs acted on L-type channels and group II mGluRs affected N-type channels. About two thirds of the responsive neurons were sensitive either to group I or group II mGluRs, whereas a minority of cells showed effects to agonists of both groups, indicating a variable mGluR expression pattern., Conclusions: Group I and group II mGluRs are expressed in human dentate gyrus neurons and modulate L- and N-type HVA channels, respectively. The data shed light on the possible cellular sequelae of the mGluR1 upregulation observed in human epileptic dentate gyrus as well as on possible mGluR-mediated anticonvulsant mechanisms.

Tiagabine is currently recommended mainly as add-on therapy in adults and children above 12 years with partial epilepsy not satisfactorily controlled with other antiepileptic drugs. Based on available evidence and our clinical experience, tiagabine should be used preferably in patients sharing one or more of the following additional features, (i) a history of drug-induced cutaneous adverse events; (ii) mild to moderate epilepsy allowing for a slow titration and gradual onset of anticonvulsant action over a few weeks; (iii) patients for whom it is particularly important to avoid a deterioration in cognitive performance; and, (iv) patients who failed to respond to previous treatment with sodium channel blocker agents as they may particularly benefit from the introduction of tiagabine, due to its GABAergic mechanism of action. Tiagabine can also be used successfully in other patients with refractory partial epilepsy. Tiagabine is not indicated for patients with generalized or unclassified epilepsies and for patients with severely impaired liver function.

A prospective cohort analysis of premenopausal women with focal epilepsy was conducted in order to determine whether polycystic ovary syndrome (PCOS) is a common finding in women treated with antiepileptic drugs (AED). This study was carried out in 93 of 150 women (aged between 20 and 53 years; mean, 34.3 years) with chronic focal epilepsy consecutively cared for at the Department of Epileptology, University of Bonn: 38 were receiving one AED (18 valproate, 20 carbamazepine), 36 more than one drug, and 19 were without medication. Patients were followed-up for 6 months. PCOS was defined as hyperandrogenism (testosterone concentration, > 0.7 ng/ml) combined with oligomenorrhoea (cycle length, > 35 days) or amenorrhoea. PCOS was identified in two out of 19 (10.5%) patients receiving no medication; in four of 38 (10.5%) of patients receiving monotherapy, and in none of the patients receiving more than one AED. The incidence of PCOS in patients treated with valproate monotherapy (11.1%) was similar to that in patients treated with carbamazepine (10%) and also to that in patients not treated with AEDs. The results of this study suggest that the manifestation of PCOS in women with focal epilepsy is not related to the administration of valproate or carbamazepine.

If continuous seizure activity lasts longer than 5 minutes generalized tonic-clonic seizures require prompt treatment, if significant morbidity and mortality are to be avoided. The mortality varies (mean: 20%) depending on patient age and etiology. Control of status epilepticus is achieved by benzodiazepines in about 80% of cases: Lorazepam is recommended due to its longer-acting effects on the central nervous system. To maintain the anticonvulsive effect phenytoin is usually administered intravenously. Fosphenytoin (not approved in Germany) has advantages over phenytoin, because it can be given three times more rapidly and produces fewer side effects. The IV use of valproic acid in status epilepticus seems to be promising, but needs further evaluation. There is no generally accepted treatment protocol for the therapy of persistent seizure activity lasting more than 60 minutes (i.e., refractory status epilepticus). Usually phenobarbital, or general anesthesia with thiopental or pentobarbital are treatment recommendations. In recent reports, the administration of midazolam or propofol proved to be effective and well-tolerated.

Purpose: This study addressed the efficacy of flumazenil (FMZ) to induce or activate interictal or ictal epileptic discharges in patients with medically intractable partial epilepsies., Methods: Flumazenil, 1 mg, was injected intravenously in 67 patients undergoing presurgical monitoring for epilepsy surgery, 49 of whom had been treated with benzodiazepines (BZDs) before flumazenil was given. Continuous video electroencephalogram (EEG) monitoring with surface or intracranial electrodes was used to evaluate interictal EEG activity, ictal discharges, and the occurrence and semiology of clinically manifest epileptic seizures., Results: Interictal epileptiform potentials did not change in frequency or distribution after FMZ. In patients not pretreated with BZDs, epileptic seizures could not be provoked. In eight of the 49 patients pretreated with BZDs, epileptic seizures occurred within 30 min of FMZ application. Seizure semiology and regional EEG onset were identical to seizures recorded without FMZ. Patients operated on according to seizure-onset localization with FMZ had a >75% reduction in seizure frequency or became seizure free., Conclusions: Seizure induction by FMZ seems to be a valid method for evaluating seizure semiology and localization of the seizure-onset zone during presurgical monitoring of patients with medically intractable localization-related epilepsies.

Purpose: Long-term treatment with carbamazepine (CBZ) may alter serum lipoprotein concentrations. Gender-related examinations, however, are rare and inconsistent in their results., Methods: To examine possible sex differences, serum lipoproteins were analyzed in 127 clinic outpatients (56 women and 71 men) with epilepsies with focal or secondarily generalized tonic-clonic seizures (or both) treated with a CBZ monotherapy. Results were compared with a control group of 177 blood donors (67 women and 110 men) matched for age and weight., Results: Total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were higher in both male and female patients treated with CBZ compared with controls. The known sex difference in serum lipoprotein concentrations (i.e., higher LDL cholesterol and triglycerides but lower HDL cholesterol in men) was confirmed in controls and patients treated with CBZ, with the exception of LDL cholesterol. The HDL as well as the LDL differences were significantly more pronounced in women treated with CBZ than in men when compared with their controls. These results were independent of the dose of CBZ and plasma concentrations. Lathosterol, a cholesterol precursor, and its ratio to cholesterol, an indicator of cholesterol synthesis, were not different, when compared between gender and different HDL groups., Conclusions: The observed increase in HDL cholesterol in patients with CBZ, especially in women, might correlate with the previously reported diminished rate of death from coronary heart disease in patients with epilepsy as HDL exerts an antiatherogenic effect.

Purpose: Carbamazepine (CBZ) is a well-established drug in the therapy of temporal lobe epilepsy (TLE). The anticonvulsant action of CBZ has been explained mainly by use-dependent effects on voltage-dependent Na+ channels in various nonhuman cell type. However, it is unclear whether Na+ currents in neurons within the focal epileptogenic area of patients with medically intractable TLE show similar characteristics., Methods: Therefore we used the whole-cell patch-clamp technique to investigate the effects of CBZ on voltage-dependent Na+ currents in 23 acutely isolated dentate granule cells (DGCs) from the resected hippocampus of eight patients with medically intractable TLE., Results: As in findings in animal preparations, CBZ significantly reduced the amplitude of the Na+ current and significantly shifted the current-voltage dependence of the steady-state inactivation in the hyperpolarizing direction. In contrast, the rapid component of the recovery from inactivation of the Na+ currents was not affected by CBZ. In addition, the reduction of the Na+ current amplitude observed during repetitive stimulation with depolarizing pulses was not significantly altered by CBZ., Conclusions: In summary, CBZ strongly affects the voltage-dependent steady-state inactivation, with no effects on the removal of inactivation in Na+ currents of human DGCs. In spite of the lack of suitable control material, the CBZ insensitivity of the removal of inactivation may be an interesting concept to explain the medically intractable TLE in these patients.

Long-term antiepileptic drug (AED) treatment is the standard therapy for epilepsies. In about 60% of patients, the first AED tried usually leads to seizure control. After failure of the first AED, it is important to achieve seizure control rapidly and without side effects. Combining the first drug with an add-on drug appears to be more effective than a second monotherapy. However, no scientifically based data are available that favor any particular drug combination. Along with pharmacokinetic considerations, clinical experience is an important determinant in choosing a second AED for use as an add-on. The time needed to introduce a particular AED is a further consideration. The simultaneous introduction of two add-on drugs, one requiring slow titration and one permitting rapid introduction, may be a useful strategy. If the quickly introduced drug is effective as an add-on, introduction of a slowly titrated second add-on can be obviated. If the quickly introduced drug reduces seizure frequency, the patient's quality of life is improved during titration of the second add-on. If the second, slowly titrated drug is more effective than the quickly introduced one, the less-effective drug can be withdrawn. This strategy also allows a direct comparison between two add-on drugs at the same time.

The aim of the study was to find out the percentage of patients with localization-related epilepsy achieving complete seizure control with gabapentin (GBP) add-on therapy. Patients under anti-epileptic drug monotherapy during 8 weeks baseline (BSL) with 6 or more seizures were treated with GBP for 26 weeks up to 2400 mg/day. Patients obtaining complete seizure control of all seizures or any partial seizure type during the last 8 weeks were calculated. Seizure frequency was compared between BSL and last 8 weeks. In all, 110 patients were enrolled (92 completed, 18 discontinued): mean age of the completers: 37.6 years (range 16-72), median seizure frequency per 28 days at BSL: 6.8 (2.5-24.5), mean duration of epilepsy: 17.6 years (0.2-51.4), mean duration with GBP for completers: 182.8 days (144-187). Complete seizure control of all seizures was achieved in 8.7% of patients (simple partial seizures: 13.3%, complex partial seizures 24.3%, secondarily generalized seizures: 61.5%): 38% of the patients became seizure-free in at least 1 seizure-type; 40% experienced adverse events. Assessment for quality of life (QoL) and trough plasma levels of GBP did not correlate with the good effect of GBP.

Purpose: To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone-binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs., Methods: Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17alpha-hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin-like growth factor-I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid-stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men., Results: In the female patients, TSH, DHEAS, follicular-phase LH, and luteal-phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17alpha-hydroxyprogesterone, free testosterone, inhibin B, and the testosterone/LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone/LH ratio in 50% indicates an impaired Leydig's cell function., Conclusions: The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17alpha-hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.

New antiepileptic drugs have been developed and released for the treatment of chronic focal and secondarily generalized epileptic seizures. The anticonvulsant efficacy of these drugs (vigabatrin, lamotrigine, gabapentin, felbamate, tiagabine, topiramate and oxcarbazepine) does not seem to be superior to that of traditional anticonvulsants. The main advantage of these newly developed drugs is a different spectrum of possible adverse events (i.e. these drugs usually do not induce sedation). Moreover, interactions with traditional anticonvulsants are less common, therefore, comedication with these drugs shows an improved tolerability. The availability of new antiepileptic drugs enables us to establish an individually tailored anticonvulsant strategy for each patient.

Valproate is a frequently used antiepileptic drug. It is associated with rare but serious adverse effects like liver failure. The first symptom is impairment of the patient's well being. Isolated changes of standard laboratory liver parameters are not reliable early indicators. Thus, according to the knowledge of today, prophylactic blood screening cannot predict complications. On the contrary, clinical symptoms are the most relevant indicators of impending complications, eventually supported by laboratory findings. An abrupt withdrawal of valproate and administering carnitin in parallel can interrupt the otherwise fatal course of the complication and induce a subsequent recovery. At a Consensus Conference the current knowledge about early detection and therapy of the valproate-induced serious hepatotoxicity was discussed. The results regarding recommended laboratory screening, as well as diagnostic and therapeutic strategies are reported.

Purpose: The anticonvulsants phenytoin (PHT), carbamazepine (CBZ), and gabapentin (GBP) are commonly used in the treatment of temporal lobe epilepsy. Ca2+ current modulation has been proposed to contribute to the antiepileptic activity of these drugs. The purpose of this study was to determine the effects of these anticonvulsants on voltage-dependent calcium channels in pathologically altered neurons from patients with chronic temporal lobe epilepsy., Methods: Acutely isolated human hippocampal granule cells were examined by using the whole-cell configuration of the patch-clamp technique., Results: PHT and CBZ produced a reversible, concentration-dependent inhibition of high-voltage-activated (HVA) Ca2+ currents without affecting voltage-dependent activation. The concentration-response curves of PHT and CBZ indicated maximal inhibition of 35 and 65%, respectively, with half-maximal inhibition being obtained at 89 and 244 microM, respectively. At therapeutic cerebrospinal fluid (CSF) concentrations, HVA currents were not significantly altered by PHT and CBZ. However, PHT but not CBZ showed a reduction of HVA currents of 16% at a therapeutic whole-brain concentration of 80 microM. In contrast to CBZ, PHT produced a small hyperpolarizing shift in the voltage dependence of steady-state inactivation. PHT, 80 microM, shifted the potential of half-maximal inactivation by -3.1 +/- 0.5 mV (p < 0.05). GBP, which was recently found to bind to the alpha2delta subunit of a neuronal Ca2+ channel, showed no modulation of Ca2+ conductances., Conclusions: These results suggest that, in contrast to GBP and CBZ, modulation of postsynaptic Ca2+ channels can contribute to the anticonvulsant action of PHT in human hippocampal granule cells.

Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.

The development of new antiepileptic drugs in recent years has enlarged the number of anticonvulsant compounds for the treatment of intractable focal epilepsies. The anticonvulsant potency of these drugs is usually compared by the number of patients who achieve a reduction in seizure frequency of more than 50%. Such an effect can be observed in approximately 20-30% of patients with pharmacoresistant focal epilepsies and is about the same with all the new compounds. In addition to the influence on focal seizures some of the novel anticonvulsant drugs exhibit efficacy in generalized seizures or in Lennox-Gastaut syndrome. In general there are fewer side effects in newly developed drugs than in standard anticonvulsants. However, in some cases characteristic side effects may occur: weight gain, depression or psychosis from vigabatrin; lamotrigine may provoke allergic rashes and felbamate may cause gastrointestinal side effects and sleeplessness. Apart from felbamate, there are no interactions with an antiepileptic comedication or they are of little importance. The development of the new anticonvulsants follows a rational design based on pathophysiological aspects: the main aim is to influence synaptic transmission, resulting in an increase in inhibitory and a decrease in excitatory transmitters. Thus, vigabatrin and tiagabine enhance the endogenous GABA amount, whereas felbamate and remacemide interact with the NMDA-receptor complex. Because it is not possible to draw sufficient conclusions from add-on studies in clinical testing it is necessary to establish new forms of trial design. Monotherapy designs are favored because they lack possible interactions with comedication and make the anticonvulsant efficacy of the compound better comparable to those of established anticonvulsants.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 27 patients with medically intractable complex partial seizures has been investigated for effects of anticonvulsant drugs on mental abilities, particularly on verbal memory performance. Fourteen patients with right (RTLE) and 13 with left (LTLE) temporal lobe epilepsy have been tested with a word list learning paradigm under the conditions of full and reduced anticonvulsant medication. Memory performance has significantly improved with drug reduction, however only for the LTLE group. In addition, significant group differences for verbal memory between LTLE and RTLE subjects under full medication have completely disappeared with drug reduction. Finally this investigation demonstrates, that very specific and circumscribed steps of verbal memory processing, particularly retrieval abilities after interference, are affected by anticonvulsants. These findings underline the importance of pharmacological effects on cognition and suggest to reevaluate their relevance compared to other contributing factors.

Thirteen patients with intractable complex partial seizures of left temporal lobe origin were tested for verbal memory performance under the conditions of full and reduced anticonvulsant medication. As suggested by previous investigations memory performance improved significantly with the reduction of anticonvulsants. However, our observations refute assumptions that the effects of antiepileptic drugs act primarily by non-specific mechanisms affecting attention and/or memory diffusely. Our data rather suggest that very specific and circumscribed steps of verbal memory processing, particularly retrieval abilities after interference, are affected by anticonvulsants. The possible implications of these findings in relation to morphological and electrophysiological aspects in patients with temporal lobe epilepsy are discussed.

Magnetic motor-evoked potentials were recorded in 53 patients with medically intractable, mainly temporal lobe epilepsy and compared with potentials of 110 healthy volunteers. The motor-evoked potentials were reevaluated in 16 of the 53 patients after substantial reduction of antiepileptic drug doses. The objective was to assess the effect of epilepsy and of anticonvulsant medication on the central motor system. In subjects receiving antiepileptic treatment, cortical threshold intensities were markedly elevated and peripheral latencies were prolonged. Cortical threshold intensities and peripheral latencies decreased to approach control values after anticonvulsant medication was reduced but were increased in patients treated with 2 or 3 anticonvulsant agents instead of 1. Additionally, high levels of interictal epileptiform activity and a high frequency of seizures significantly decreased the central motor conduction time and, in part, threshold intensities. The central motor conduction time was further diminished after reduction of anticonvulsant treatment and increased when several drugs were administered. The duration of epilepsy, the location of the epileptic focus, and the type of the epileptic seizure did not affect motor-evoked potentials. Conclusively, central motor pathways are endogenously facilitated by epileptiform activity even if clinical signs of their involvement are absent. Anticonvulsant medication exerts major reversible effects on magnetic motor-evoked potentials.

Background: Functional hemispherectomy is a well-established method in childhood epilepsy surgery with only a few reports on its application in adults. Methods: We report on 27 patients (median age 30 years, range 19-55) with a follow-up of more than 1 year (median 124 months, range 13-234). Etiology was developmental in two (one schizencephaly, one hemimegalencephaly), acquired in 21 (two hemiatrophy, 17 porencephaly, two postencephalitic), and progressive in four (Rasmussen's encephalitis). Results: At last available follow-up, 22 patients were seizure free (81 % ILAE class 1), one had auras (4 % ILAE class 2), one had no more than three seizures per year (4 % ILAE class 3). Thirty-seven percent were without antiepileptic drugs. Seventeen patients of 20 responding patients stated improved quality of life after surgery, one patient reported deterioration, and two patients reported no difference. Additionally, a self-rated postoperative functional status and changes compared to the pre-operative status was assessed. Six patients improved in gait, ten remained unchanged, and four deteriorated. Three patients improved in speech, none deteriorated. Hand function got worse five times, and in 15 cases remained unchanged. There was no mortality, one bone flap infection, and one subdural hematoma. Hydrocephalus was seen in three cases (12 %). Conclusions: It is possible to achieve good seizure outcome results despite long-standing epilepsy across a variety of etiologies, comparable to epilepsy surgery in pediatric patients. Adult patients do not have to expect more problems with new deficits, appear to cope quite well, and mostly profit from surgery in several quality of life domains. [ABSTRACT FROM AUTHOR]

Objectives – The aim of the study was to evaluate the influence of precipitating factors and therapy on the outcome of epilepsy with generalized tonic–clonic seizures. Patients and methods – Retrospective analysis of data from 34 patients (mean age at seizure onset 19 years; mean duration of follow‐up 9.2 years) suffering from epilepsy of either cryptogenic or remote symptomatic (n=19), or idiopathic (n=15) etiology. The total number of seizures in all patients was 146. Results – Without treatment 97 seizures manifested during 90.5 years without treatment (1.07 seizures/year), during treatment with carbamazepine or valproate 49 seizures occurred within 224 years (0.2 seizures/year). The frequency of seizures was significantly lower during treatment. Precipitating factors were found in relation to 31% of seizures in patients with remote symptomatic or cryptogenic epilepsy, and for 51% of seizures in patients with idiopathic epilepsy. Conclusions – There was a low frequency of seizures in patients with generalized tonic–clonic seizures. Precipitating factors are common. Antiepileptic drug treatment is effective. [ABSTRACT FROM AUTHOR]