Felbamate monotherapy: controlled trial in patients with partial onset seizures.

Felbamate (FBM) monotherapy was evaluated in 44 patients with uncontrolled partial onset seizures in a unique, single-center, randomized, double-blind, parallel-group trial. During the 56-day baseline period, patients were required to have at least 8 seizures and to be receiving only one standard antiepileptic drug (AED) at a therapeutic level; a second AED was allowed if at a subtherapeutic level. Patients were randomized to valproate (VPA), 15 mg/kg, or to FBM, 3,600 mg/day. In the treatment phase, previous AEDs were discontinued by study day 28 (by one-third decrements on study days 1, 14, and 28). Study end points were completion of 112 study days or the fulfilling of escape criteria. Criteria for escape relative to baseline were: two-fold increase in monthly seizure frequency, two-fold increase in highest 2-day seizure frequency, single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or significant prolongation of GTCs. The predetermined primary efficacy variable was the number of patients escaping in each treatment group. Nineteen patients on VPA and 3 on FBM met escape criteria (p less than 0.001, chi-square test). When overall seizure frequency among study completers was compared with baseline, the FBM group had a 50 to 65% reduction in seizure frequency. FBM adverse experiences were all mild or moderate in severity, and the incidence of adverse experiences was lower in monotherapy. FBM monotherapy was effective in the treatment of partial onset seizures with or without generalization and demonstrated a favorable safety profile.     

The efficacy of felbamate as add-on therapy to valproic acid in the Lennox-Gastaut syndrome

We studied the efficacy of felbamate (FBM) in combination with valproic acid (VPA) in 13 patients with the Lennox-Gastaut syndrome and evaluated the contribution of each drug. Following stabilization on VPA monotherapy, FBM or placebo titration was performed for two observation periods lasting 7 weeks with a washout period between them. 6-h video-electroencephalography was recorded following each observation period. In addition to examining the effects of the drugs with parental reports and video-EEG, we compared video-EEG data with families' seizure reports. Based on parental counts for the 7-week observation periods, patients had 40% fewer drop attacks (p < 0.03, Wilcoxon rank sum test) and 60% fewer total seizures (p < 0.02) on VPA and FBM. VPA level rose by 12.7% when FBM was added (p < 0.01). When the effect of FBM was factored out, VPA had a significant effect on drop attack frequency, although not total number of seizures. FBM's therapeutic effect on drop attacks is due in part to increased VPA levels, although the combination may be synergistic for the effect on total seizure number.     

Felbamate in the Treatment of Partial-Onset Seizures

Summary: Felbamate (FBM, Felbatol/Taloxa) has been the object of several trials that are innovative and unique. First, FBM is the first antiepileptic drug (AED) to have been submitted to a controlled efficacy study in patients with the Len-nox-Gastaut syndrome (LGS) before being submitted for regulatory approval. Second, FBM was tested in patients discontinued from other AEDs for presurgical monitoring. Third, FBM was the first experimental AED to have been tested in controlled monotherapy trials. Overall, these studies succeeded in demonstrating that FBM is relatively safe and effective against both partial-onset seizures and the generalized seizures occurring in the LGS. The results of some of these studies could not always be expressed by using the more familiar concept of percent seizure reduction because, for ethical reasons, the efficacy variable had to be defined in terms of time to the n^lh seizure or in terms of escape criteria. This may make it more difficult to evaluate just how effective FBM is in comparison with other AEDs. Another reason why the efficacy of FBM cannot yet be fully assessed is that in all the studies the FBM dosage was limited to a maximum of 3,600 mg/day or 45 mg/kg/day. At this dosage, FBM produced no toxicity in the majority of patients, and its full therapeutic effect may have to be re-evaluated in the future at higher dosages.     

Double-Blind Crossover Trial of Progabide Versus Placebo in Severe Epilepsies

In this double-blind, two-period, crossover trial with randomized treatment assignment, progabide (+/- 30 mg/kg/day) and placebo were compared as add-on to standard therapy in 20 "therapy-resistant" epileptic patients (11 males, nine females; age range, 7-47 years). The duration of each treatment period was 6 weeks. Crossover was performed gradually over 3-4 days. Twenty-four patients entered the study: three dropped out for reasons unrelated to progabide effects; one dropped out during the placebo period because of increased seizure frequency. Of the 20 patients who completed the study, 14 had partial, two partial plus secondary generalized, and four generalized seizures. Preexisting antiepileptic treatment consisted of one antiepileptic drug (AED) in three, two AEDs in eight, three AEDs in five, and four AEDs in four patients (mean, 2.5 AEDs/patient). The following parameters were recorded at biweekly intervals: (a) efficacy parameters--total seizure count, counts of each seizure type, and global clinical judgment; (b) safety parameters--adverse drug effects, brief clinical and neurological examinations, and laboratory tests; and (c) plasma concentrations of progabide and of the associated AEDs. Twelve patients were considered to be improved (p less than 0.01) with progabide by global clinical judgment compared with two patients improved with placebo. Nine patients of 20 had a 48-100% reduction of total seizure count in the verum period, leading to a significant reduction of total seizure number and of complex partial seizures in the verum period as compared with the placebo period (p less than 0.05). Adverse effects were reported or observed in 10 patients during the progabide period and in five patients in the placebo period. The side effects were generally mild and consisted of somnolence in four cases and of tremors, dry mouth, troubles of equilibrium, anorexia, euphoria, depression, and anxiety in individual patients; a 15-20% reduction of the progabide dose was required in two cases only. No treatment-related alterations in results of laboratory tests were observed.     

Felbamate in the Treatment of Refractory Partial-Onset Seizures

Summary: Felbamate (FBM) is a new antiepileptic drug (AED) that has been tested in open and controlled studies in patients with therapy-refractory partial-onset seizures. Proof of efficacy is based on results of five controlled studies (three with polytherapy and two with monotherapy). In two of the three polytherapy studies, a classic placebo crossover design was used. The third study used a novel design evaluating the efficacy of FBM in a placebo-controlled parallel design in patients completing an evaluation for epilepsy surgery. The primary efficacy variable in this study was the number of patients who experienced a fourth seizure before the end of the study. Forty-six percent of patients randomized to FBM stopped treatment prematurely because of the occurrence of a fourth seizure compared with 88% randomized to placebo. Two studies investigating the efficacy in monotherapy were performed. Both studies used an identical trial design comparing FBM with a low dosage of valproate (VPA). The efficacy of FBM was found to be superior to the low-dosage VPA for both studies. Open long-term follow-up studies have confirmed the long-term efficacy of FBM for up to 12 months. Overall, FBM was well tolerated in both poly- and monotherapy.     

A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures

Purpose: Efficacy and safety of adjunctive rufinamide (3,200 mg/day) was assessed in adolescents and adults with inadequately controlled partial‐onset seizures receiving maintenance therapy with up to three antiepileptic drugs (AEDs). Methods: This randomized, double‐blind, placebo‐controlled, parallel‐group, multicenter study comprised a 56‐day baseline phase (BP), 12‐day titration phase, and 84‐day maintenance phase (MP). The primary efficacy variable was percentage change in total partial seizure frequency per 28 days (MP vs. BP). Secondary efficacy outcome measures included ≥50% responder rate and reduction in mean total partial seizure frequency during the MP. Safety and tolerability evaluation included adverse events (AEs), physical and neurologic examinations, and laboratory values. Pharmacokinetic and pharmacodynamic assessments were conducted. Results: Three hundred fifty‐seven patients were randomized: 176 to rufinamide and 181 to placebo. Patients had a median of 13.3 seizures per 28 days during BP; 86% were receiving ≥2 AEDs. For the intent‐to‐treat population, the median percentage reduction in total partial seizure frequency per 28 days was 23.25 for rufinamide versus 9.80 for placebo (p = 0.007). Rufinamide‐treated patients were more than twice as likely to have had a ≥50% reduction in partial seizure frequency (32.5% vs. 14.3%; p < 0.001) and had a greater reduction in median total partial seizure rate per 28 days during the MP (13.2 vs. 5.2; p < 0.001). Treatment‐emergent AEs occurring at ≥5% higher incidence in the rufinamide group compared with placebo were dizziness, fatigue, nausea, somnolence, and diplopia. Conclusions: Adjunctive treatment with rufinamide reduced total partial seizures in refractory patients. AEs reported were consistent with the known tolerability profile of rufinamide.     

Felbamate in the Treatment of Lennox-Gastaut Syndrome: Results of a 12-Month Open-Label Study Following a Randomized Clinical Trial

Summary: Felbamate (FBM) is a new antiepileptic drug (AED) that has been evaluated in partial seizures and in the Lennox-Gastaut syndrome (LGS). When tested against placebo in an add-on, randomized, double-blind trial in 73 children with LGS, FBM significantly reduced the frequencies of astatic (atonic) seizures and generalized tonic-clonic seizures plus total seizure counts. In addition, FBM-treated subjects improved significantly on a parent-rated global evaluation and had fewer injuries. Overall, ˜50% of subjects experienced a 50% or greater reduction in total seizure frequency and a dose-response relationship was apparent. The improvement that occurred in the double-blind study has been sustained for at least 12 months in subsequent open-label follow-up studies. In the first month of FBM treatment, 62% of the subjects who had previously received placebo had a reduction in total seizure frequency of >50%. By the 12-month follow-up point, approximately half of the patients had a 50% reduction in total seizure count. Astatic seizures responded even better, with two-thirds of patients having a reduction of >50% in astatic seizure frequency after 12 months of treatment. Based on adverse experience reports thus far, FBM appears to be well tolerated. FBM is the first drug to be shown effective in the LGS in randomized controlled trials. Although few subjects with LGS became seizure free, the frequency of the most severe seizure types decreased and the patients' global functioning improved.     

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.     

Tiagabine Monotherapy in the Treatment of Partial Epilepsy

Summary: Three studies were conducted to assess tiagabine (TGB) hydrochloride monotherapy in patients with partial seizures. The first was a double-blind, placebo-controlled trial of 11 patients (seven TGB, four placebo) undergoing evaluation for epilepsy surgery. Baseline antiepileptic drug (AED) therapy was discontinued abruptly before monotherapy. Although 24-h seizure rates increased during monotherapy in both groups, patients receiving TGB experienced fewer seizures than placebo patients. Subsequent studies (an open-label, dose-ranging study; n = 31 and a double-blind, randomized comparison of 6 and 36 mg/day TGB; n = 102 and 96, respectively) involved discontinuation of baseline AEDs. In the dose-ranging study, 19 of 31 patients (61%) converted to TGB monotherapy, with a mean final dose of 38.4 mg/day (range 24–54 mg/day) in those who completed the study ( n = 12). In the low- vs. high-dosage study, median 4-week complex partial seizure rates decreased significantly in patients from both dose groups who completed the monotherapy period ( p <0.05 compared with baseline). In the intent-to-treat analysis, significantly more patients in the high-dose group experienced a reduction in seizures of at least 50% compared with the low-dose group ( p = 0.038). Overall, the types of adverse events with TGB monotherapy were similar to those observed in add-on trials. These initial trials in difficult-to-treat epilepsy patients indicate that TGB monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other AEDs.     

Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). BACKGROUND: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. DESIGN: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30-46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. METHODS: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. RESULTS: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. CONCLUSION: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.     

Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Purpose: To assess the efficacy and safety of once‐daily doses of perampanel 8 and 12 mg when added to 1–3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures. Methods: Study 305 was a multicenter, double‐blind, placebo‐controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1–3 AEDs. Equal randomization to once‐daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19‐week double‐blind treatment phase comprising a 6‐week titration period, with weekly 2‐mg dose increments, followed by a 13‐week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre‐perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty‐six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent‐to‐treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent‐to‐treat analysis) was ?9.7%, ?30.5%, and ?17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was ?32.7% (8 mg), ?21.9 (12 mg), and ?8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment‐emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once‐daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial‐onset seizures. These study results also demonstrated that once‐daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.     

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001).The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.     

Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study

PURPOSE: To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. METHODS: Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-aeg/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7-day period after the operation. RESULTS: Of 100 patients allocated to PHT, 13 experienced seizures during the 7-day observation period, compared with 11 of 100 patients in the placebo group (p > 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT-treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT-treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred. CONCLUSIONS: PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.     

Effects of Tiagabine Monotherapy on Abilities, Adjustment, and Mood

Summary: Purpose: We evaluated the dose-related impacts of tiagabine (TGB) on cognition and mood in a monotherapy study.
Methods: Patients were 123 adults with uncontrolled partial seizures, each treated with a single currently available antiepileptic drug (AED) for management of clinical epilepsy. They completed a battery of neuropsychological tests during an 8 week prospective baseline period and once again at the end of the 12-week fixed-dose period (or earlier if they dropped out of the study). Sixty-six patients were randomized to 6 mg/day TGB and 57 were randomized to 36 mg/day TGB.
Results: Few changes in either abilities or adjustment and mood were noted when all patients were considered as a single group. However, analysis of both dose and attainment of TGB monotherapy showed that patients receiving TGB monotherapy did best, improving particularly in the areas of adjustment and mood with low-dose TGB and in the area of abilities with high-dose TGB. Patients who did not attain monotherapy showed no change except that the high-dose group did not perform as well on measures of mood and adjustment. Baseline AED and changes in seizure control did not affect the results.
Conclusions: Patients attainment of TGB monotherapy was associated with their achievement of positive changes of varying degree on psychological tests. Failure to attain TGB monotherapy was associated with no changes on the tests except in patients receiving high-dose TGB where it appeared that some alterations in mood might have been avoided if a slower titration schedule had been used.     

Levetiracetam monotherapy for elderly patients with epilepsy.

We retrospectively identified 14 elderly patients with a history of partial seizures who received levetiracetam (LEV) monotherapy. Patients began LEV either as first line therapy (n=5) or were converted to LEV monotherapy (n=9) after failing prior antiepileptic medications (AEDs). Thirteen patients continued on LEV monotherapy for at least 6 months. One patient was lost to follow-up. Eight patients (61.5%) became seizure free. Four patients who began LEV as a first line therapy became seizure free, whereas the remaining four patients who converted to LEV after they failed their previous AEDs became seizure free. Four patients (30.7%) had more than a 50% seizure reduction of seizures. Only one patient had no significant change in seizure frequency after started on LEV. The total dosages used to control seizures were 500-3000 mg/day, (mean 1839.2 mg/day). LEV monotherapy can be effective and well tolerated in this group of patients. A prospective, larger, double blind monotherapy study is needed to confirm this finding.     

Therapeutic intensive seizure analysis (TISA) in presurgical evaluation of Losigamone

OBJECTIVE: The new method TISA was used to evaluate Losigamone efficacy. METHODS: Sixteen patients with pharmacoresistant partial seizures undergoing presurgical evaluation were randomized in this double-blind, placebo-controlled, parallel-group Losigamone monotherapy study under continuous video-EEG monitoring. Duration (in s, of each seizure and each ictal sign), intensity (grade zero to three), N/24h (number of seizures and ictal signs per 24 h), D/24h (seconds per 24 h covered by seizures and ictal signs) and seizure free intervals were recorded. RESULTS: A total of 246 seizures were intensively analyzed. The duration and intensity of all seizures improved more in the active treatment group than in the placebo group. There was a statistically significant superiority in the duration of the seizure free interval in the Losigamone group. Ictal signs such as oro-alimentary automatisms and fumbling were improved during Losigamone treatment. CONCLUSION: Losigamone has a preferred inhibitory effect on propagated epileptic activity. TISA is a sensitive method for evaluation of the selective effects of AEDs.     

Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures

The efficacy and safety of felbamate monotherapy were evaluated in 52 patients with refractory partial seizures with or without secondary generalization in a double-blind, randomized, placebo-controlled trial. Each patient completed a routine evaluation for epilepsy surgery and was randomized to receive either felbamate, titrated to a maximum daily dose of 3600 mg over 2 days, or placebo during the 10-day, inpatient, treatment phase. An intent-to-treat analysis was performed on the data of all 52 patients who received study medication, while a separate efficacy analysis also was performed on the data of 43 evaluable patients, which excluded protocol violators. The endpoint of the trial was completing 10 days of treatment or the occurrence of a fourth seizure. The primary efficacy variable was the average daily seizure frequency during the treatment phase for each patient. For the intent-to-treat analysis based on all 52 patients who received study medications, the mean rank of the daily seizure frequency for patients treated with felbamate was 21.6 compared to 29.6 for patients treated with placebo (P = 0.065). In the analysis based on the 43 evaluable patients, the mean rank of the daily seizure frequency for felbamate-treated patients was 17.0 compared to 25.4 for placebo-treated patients. This difference was statistically significant (P = 0.032) in favor of felbamate. Seizure frequency was decreased by 89.5% compared to baseline in nine patients who completed 10 days of felbamate therapy. This study permitted the rapid determination of the anticonvulsant activity of felbamate and demonstrated that felbamate is effective as monotherapy for the treatment of partial seizures.     

Felbamate in the Treatment of Lennox-Gastaut Syndrome

Summary: Felbamate (FBM, Felbatol/Taloxa), a new an-tiepileptic drug (AED), was tested in a placebo-controlled add-on design in 73 patients with therapy refractory Lennox-Gastaut syndrome. Results of the efficacy analysis showed that FBM was statistically significantly more effective (p < 0.05) than placebo for four of five predefined efficacy variables. The total number of seizures, for example, decreased by 26% during treatment with FBM compared with an increase of 5% during placebo (p < 0.001). Retrospective analysis of percentage of patients with specific response rates confirmed results of the predefined efficacy variables. Approximately 50% of patients randomized to FBM obtained at least a 50% reduction in seizure frequency compared with about 15% receiving placebo. In addition, 12-month follow-up data in patients who completed the controlled part of the study confirmed the long-term efficacy of FBM. In general, FBM was well tolerated, with only gastrointestinal symptoms and somnolence seen more often with FBM compared with placebo. FBM is the first compound shown to be effective in a controlled study in patients with Lennox-Gastaut syndrome.     

Topiramate Monotherapy for Partial Onset Seizures

Summary: Purpose: Evaluation of topiramate (TPM) as monotherapy in patients with uncontrolled partial onset seizures.
Methods: A total of 48 patients were evaluated in a doubleblind, parallel-group trial. During a 56-day baseline period, patients had at least eight partial onset seizures while being treated with one or two standard antiepileptic drugs (AEDs). After 1–2 weeks of open-label treatment with TPM 100 mg/day, patients were randomly assigned, in equal proportions, to receive double-blind therapy with TPM 100 or 1,000 mg/day in a 5-week conversion and an 11-week monotherapy period. The study endpoint was completion of 112 study days (success) or fulfillment of one or more exit criteria: doubling of average 28- day or highest 2-day baseline seizure rate, a generalized tonic-clonic seizure (GTCS) if none had occurred at baseline, or significant prolongation of generalized seizure duration.
Results: Time until exit was longer (p = 0.002) and success frequency was higher (p = 0.005) with TPM 1,000 as compared with 100 mg/day. Seizure-rate reductions of 50, 75, or 100% were achieved by 46, 25, and 13% of the 1,000-mg/day group, respectively, as compared with 13, 8, and 0% of the 100-mg/day group, respectively. Most adverse events (AE) were mild or moderate in severity.
Conclusions: Monotherapy with TPM 1,000 mg/day for partial onset seizures with or without secondarily generalized seizures was effective, with a favorable safety profile.     

Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy

BACKGROUND: In the face of availability of newer antiepileptic drugs (AEDs) such as lamotrigine and topiramate, there is need to reassess the role of older AEDs in the treatment of juvenile myoclonic epilepsy (JME). OBJECTIVES: To explore whether lamotrigine and topiramate monotherapy or polytherapy can be effective options in the treatment of JME, and to determine whether older AEDs, such as phenytoin and carbamazepine, have a role in the treatment of JME. DESIGN: A retrospective cohort study. SETTING: A large academic teaching hospital. PATIENTS: Seventy-two consecutive JME patients treated with valproic acid, lamotrigine, topiramate, phenytoin, or carbamazepine between April 1, 1991, and March 31, 2001. METHODS: We compared the efficacy of valproic acid, lamotrigine, and topiramate monotherapy or polytherapy in the control of different seizure types of JME, and compared their efficacy and tolerability with the efficacy and tolerability of phenytoin and carbamazepine. RESULTS: Seizure outcome did not differ when patients receiving valproic acid monotherapy (n = 36) were compared with those receiving lamotrigine monotherapy (n = 14), and when patients receiving valproic acid polytherapy (n = 22) were compared with those receiving lamotrigine polytherapy (n = 21) or topiramate polytherapy (n = 15) (P>.05 for all). The combined data of myoclonic seizure control by all 3 AEDs were poorer when compared with the combined data of generalized tonic-clonic seizure control by all 3 AEDs (P =.03), but not when compared with the combined data of absence seizure control by all 3 AEDs (P =.43). Valproic acid, lamotrigine, and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures (P<.01 for all), but not of generalized tonic-clonic seizures (P>.11 for all). CONCLUSIONS: Lamotrigine and topiramate are effective alternative options to valproic acid in the treatment of JME. Lamotrigine is an effective option as monotherapy and polytherapy. Topiramate is an effective option as polytherapy, but more data are needed to determine if it is an effective option as monotherapy. More effective therapy is needed to improve myoclonic seizure control. Older AEDs, such as phenytoin and carbamazepine, may not be indicated in JME patients.