Adjustment of Carbamazepine Dose to Offset the Effects of the Interaction with Remacemide Hydrochloride in a Double-Blind, Multicentre, Add-On Drug Trial (CR2237) in Refractory Epilepsy

Summary: Purpose: The efficacy of remacemide hydrochloride (REM) as an antiepileptic drug (AED) was tested in a double-blind, add-on trial in patients with refractory epilepsy. Concurrent drugs included carbamazepine (CBZ). The interfering effects of the pharmacokinetic interaction between REM and CBZ were offset by the monitoring of plasma CBZ concentration and the appropriate reduction of CBZ dose by an unblinded observer.
Methods: Patients taking CBZ entered a 4-week run-in period to stabilise their dosage regimen to Tegretol tablets and blinded capsules containing Tegretol tablets. They then entered an 8-week baseline period during which variation of plasma CBZ concentration was used to derive an individual Shewart Control Chart for each patient. These charts were used to define the threshold for CBZ dose reduction after the addition of trial drug. Where necessary the unblinded observer adjusted that portion of the daily dose of CBZ concealed in the opaque capsules, thereby maintaining the blind for the investigator and the patient.
Results: CBZ dosage reductions ranging from 14 to 50% were required by 63% of patients who received REM. Substantial increases in plasma CBZ concentration, which would have confounded the results of the trial, were thus avoided. The small increases in CBZ concentration that occurred in spite of this procedure were of similar magnitude in responders (patients who experienced ≤50% reduction in seizure frequency during treatment) and nonresponders, and in both groups the mean increase was <1 mg/L.
Conclusions: The method is offered as a model solution for problems caused by pharmacokinetic interactions in add-on trials.     

Insights into the tetanus toxin model of early-onset epilepsy from long-term video monitoring during anticonvulsant therapy

Video monitoring studies were undertaken to determine if the anticonvulsant, carbamazepine (CBZ), could prevent seizures in infant rats that had been intrahippocampally injected with tetanus toxin (TNTX). In control rats, seizure frequency peaked 5-6 days after injection and rapidly declined by postinjection day 9. Twice-daily CBZ treatments dramatically suppressed behavioral seizures for 7 days. However, despite increasing the dosage of CBZ, rats experienced more behavioral seizures during the second week after TNTX injection. Paradoxically, tetanus-toxin-injected control rats had very few seizures at this time. Results not only suggest that this TNTX model may be useful in screening drugs for treating intractable focal epilepsy of infancy but also provide some insight into the processes that may contribute to the rapid decline in behavioral seizure frequency that occurs during the acute phase of epileptogenesis in this model.     

Efficacy of Nafimidone in the Treatment of Intractable Partial Seizures: Report of a Two-Center Pilot Study

Nafimidone is a potential new antiepileptic drug with a therapeutic profile in experimental animal seizure models similar to that of phenytoin (PHT). We report here the first clinical trial of nafimidone in epileptic patients. Twelve adult male patients with a mean of four or more medically intractable seizures per month were enrolled in a 14-week pilot study. Patients were stabilized on therapeutic levels of PHT and carbamazepine (CBZ) (nine patients) or on PHT alone (three patients) before entering a 4-week baseline period. Nafimidone, to a maximum dose of 600 mg/day, was added during 2 weeks in hospital. Patients were then evaluated weekly for 8 weeks. Eight patients experienced 33-98% improvement in seizure control. Three others did not show significant change in seizure frequency but experienced sufficient subjective improvement that they continued into long-term follow-up. One patient, who had a 63% improvement in mean weekly seizures during the pilot study, declined to continue. Thus, 10 patients entered long-term follow-up. Six of the 10 sustained 53 to greater than 99% improvement in seizure control compared with baseline over the course of 46-53 weeks of follow-up. Nafimidone had a marked inhibitory effect on the clearance of CBZ and PHT, resulting in higher plasma levels in nine patients. The possible role of the elevated CBZ levels in the apparent efficacy of nafimidone is discussed.     

Maprotiline treatment in depression. A perspective on seizures

Eleven McLean Hospital (Belmont, Mass) depressed patients who experienced seizures while receiving maprotiline hydrochloride are presented, as are data on 87 cases reported to the manufacturer (Ciba-Geigy). Most seizures occurred at high dosages, sometimes after many weeks at a stable dose, but neither rapid dosage escalation nor high drug plasma levels seemed related to seizure occurrence. Our experience suggests that a long-acting metabolite might be responsible for seizures. Ten of the 11 McLean Hospital seizures occurred in patients receiving dosages outside of the since-revised current dosage guidelines, as did 60% of the seizures reported to the company. Data in this study suggest that reductions in maximum dosage of maprotiline prescribed after the initial six weeks of treatment could result in a further decrease in risk of seizures beyond that obtained from previous alterations in regimens.     

Practical Aspects of Oxcarbazepine Treatment

Summary: In patients with refractory seizures, substitution of oxcarbazepine (OCBZ) for carbamazepine (CBZ) may be associated with reduced seizure frequency and an improved mental state. The recommended dosage of OCBZ as monotherapy for adults with epilepsy is 600-1,200 mg orally per day but may be higher in patients with refractory seizures and in patients requiring combination therapy. When OCBZ is substituted for ongoing CBZ therapy, it is possible to change the dosage immediately so that the patient finishes treatment with CBZ on one day and starts with a full dosage of OCBZ on the next day, even when the full dosage is 50% greater in milligrams than the corresponding CBZ dosage. Allergic skin reactions are rare, and crossreactivity is seen in about 25% of patients hypersensitive to CBZ. Hyponatremia after the use of OCBZ is usually benign, as long as the acute water intoxication is effectively treated. Because of its pharmacokinetic advantages' and efficacy, we believe OCBZ is better than CBZ. We therefore consider OCBZ as the drug of first choice for conditions in which CBZ is currently indicated.     

Tiagabine: Efficacy and Safety in Adjunctive Treatment of Partial Seizures

PURPOSE: To assess the efficacy and safety of tiagabine (TGB), a new antiepileptic drug (AED), as add-on therapy in patients with refractory partial seizures. METHODS: This response-dependent study used an open-label screening phase (in which patients were titrated to their optimal TGB dose, < or =64 mg/day) followed by a double-blind, placebo-controlled, crossover phase. Initial eligibility criteria included (a) seizures inadequately controlled by existing AEDs, and (b) six or more partial seizures during an 8-week baseline period. Patients showing benefit from TGB (> or =25% reduction in total seizure rate relative to baseline) were eligible for randomization into the double-blind phase, which comprised two 7-week assessment periods separated by a 3-week crossover period. RESULTS: Forty-four (50%) of the 88 enrolled patients entered the double-blind phase of the study during which there were significant reductions compared with placebo in all partial (p < 0.01), complex partial (p < 0.001), and secondarily generalized tonic-clonic seizure rates (p < 0.05). Thirty-three percent of patients experienced a reduction of > or =50% in the all partial seizure rate. Eight (22%) patients receiving TGB during the double-blind phase reported adverse events, of which dizziness and incoordination were the most frequent. Three patients withdrew from treatment during the double-blind phase because of adverse events; two during treatment with TGB and one during treatment with placebo. TGB did not affect plasma concentrations of other coadministered AEDs. CONCLUSIONS: TGB was significantly better than placebo in terms of seizure rate reduction and was generally well-tolerated in patients with difficult to control seizures.     

Stiripentol in Atypical Absence Seizures in Children: An Open Trial

Summary: Stiripentol (STP) was added to the antiepileptic drug (AED) regimen of 10 patients with uncontrolled atypical absence seizures (more than one seizure a day). Seven boys and three girls aged 6–16 years participated in the study. Concomitant AEDs included various combinations of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). Parents counted daily seizures over a 4-week baseline period before institution of STP, and in a 20-week period during STP therapy. To compensate for drug interactions, doses of other AEDs were adjusted during STP administration to keep serum levels close to levels of the baseline period. Maintenance doses of STP were 1,000–3,000 mg/day, giving serum levels of 4–22 μg/mL. All patients experienced a decrease in atypical absence seizures. Average decrease was 70% (range 5–95%). Side effects experienced by some patients were dose related and included anorexia, nausea, vomiting, and lethargy. In only 1 patient did an adverse effect (vomiting) require discontinuation of STP. We conclude that STP shows promise in treatment of atypical absence seizures in children, and further trials are warranted.     

Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Summary: A recent problem for doctors has been the choice of which new antiepileptic drug (AED) to select for treatment of pharmacoresistant epilepsy. This article summarizes the clinical experience to date regarding the efficacy and safety of tiagabine (TGB; Gabitril) as adjunctive therapy in patients with partial-onset seizures. In its early Phase II development, TGB was evaluated in two multicenter pilot studies. Each had an open-label enrichment phase followed by a treatment phase with randomized, double-blind, two-period, cross-over phases. Between 24 and 50% of patients experienced reductions in seizure rates of ≥50%, depending on the type of partial seizure. In Phase III, three double-blind, parallel group, placebo-controlled adjunctive studies determined the efficacy of TGB in patients with refractory partial seizures. The first was a dose-response study employing doses of TGB-HCl of 16, 32 or 56 mg/day. Significant reductions in seizure rates were found with 32 and 56 mg/day. The second and third studies evaluated the efficacy of dosing TGB twice, three times, and four times daily, all of which showed similar efficacy. TGB efficacy in partial seizures was supported in several open trials, and no tolerance to efficacy was noted in long-term continuation studies. Tolerability was documented in all trials. Most adverse events were mild or moderate and transient, occurring during dose titration. They were clearly dose-related. No relevant changes in hematologic and biochemical tests, vital signs, or body weight were attributable to TGB. TGB appears to be an effective new drug for partial seizures with an acceptable safety profile.     

Rapid Switchover to Carbamazepine Using Pharmacokinetic Parameters

Summary: Purpose: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the singledose kinetic study can yield the desired concentration at steady state (C_ss); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period. Methods: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) andor primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean C_ss of 10.2 (±2.2) mgA. On day 2, patients received a CBZ dose equivalent to 10 mgkg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1: PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mgA was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED. Results: All patients completed the switchover to CBZ within a mean time period of 6 days (±2), reaching a mean maintenance dose of 1, 639 mg/day (±370) which yielded a mean C_SS of 11.3 (±3.2) mg/l. The maintenance dose had to be lowered by 20.4% (±8.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients 2–55 years (p = 0.017, Fisher's exact test). Conclusions: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.     

Pharmacokinetic and Dose Tolerability Study of ADD 94057 in Comedicated Patients with Partial Seizures

ADD 94057, a metabolite of fluzinamide, manufactured by the A. H. Robins Company, blocks chemically- and electrically-induced seizures in animals. The primary objective of this open add-on study was to evaluate patient tolerability of ADD 94057 at ascending target plasma concentrations. Nine subjects with medically refractory seizures were receiving phenytoin (PHT, 3), carbamazepine (CBZ, 3), or both (3). A pharmacokinetic profile after a single oral 400-mg dose of ADD 94057 was used to calculate ADD 94057 dosages. After a 4-week baseline period, patients were treated for 4 weeks with weekly ADD 94057 dosage escalations. Two patients completed the study at their assigned highest dosage level; the other patients finished the study at lower dosages. The patients receiving PHT (but not CBZ) tolerated higher plasma concentrations of ADD 94057 than did patients receiving CBZ, alone or in combination with PHT. Adverse experiences included headache, ataxia, blurred vision, diplopia, dizziness, lightheadedness, and mild confusion. Eight of nine patients had reductions in seizure frequency from baseline.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and valproate in monotherapy

PURPOSE: To quantify changes in ictal seizure semiology during rapid withdrawal of carbamazepine (CBZ) and valproate (VPA) from a monoregimen in presurgical evaluation. METHODS: Therapeutic intensive seizure analysis (TISA) with video-EEG monitoring was used in 33 patients with pharmacoresistant partial epilepsy undergoing complete withdrawal of CBZ (20 patients) or VPA (13 patients) from a monoregimen. Monitoring phases included a 3-day baseline phase, a 3-day rapid antiepileptic drug (AED) withdrawal phase, and another 3-day AED-free phase with AEDs in subtherapeutic levels. Seizure variables as complete processes and their various elements (ictal signs) were analyzed, including duration (seconds), intensity (on a scale of 0 to 3), frequency (number per 3 days), and total duration of seizures and ictal signs in 3 days (seconds). The localization of seizure patterns on ictal EEG recording (EEG seizure onset) and the first appearing clinical ictal phenomena (initial ictal signs) were recorded. RESULTS: A total of 188 seizures in the CBZ group and 57 seizures in the VPA group were investigated. Compared with the baseline phase, the CBZ group showed increases in duration, frequency of seizures, various ictal signs, and secondarily generalized tonic and clonic signs during the following two phases. Significantly increased values of the VPA group were observed in seizure duration and frequency of hypermotoric phenomena during the AED-free phase. More patients in the CBZ group had secondarily generalized clonic signs during the AED-free phase. EEG seizure onset and initial ictal signs showed no obvious changes between study phases. CONCLUSIONS: Withdrawal of CBZ is followed more quickly by an increase of seizure frequency and severity than is the case for VPA withdrawal. Both CBZ and VPA withdrawal influences seizure propagation rather than the seizure-onset characteristics, which speaks in favor of its use in presurgical evaluation.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

Changes of seizures activity during rapid withdrawal of lamotrigine

Quantitatively evaluating the rapid withdrawal effects of lamotrigine (LTG) and carbamazepine (CBZ) on seizure activity during pre-surgical evaluation in patients with pharmacoresistant complex partial epilepsy. The duration and frequency of seizure activities and electrographic seizure onset of 41 patients totally withdrawing from CBZ monotherapy (n = 20), LTG monotherapy (n = 10) and CBZ + LTG combined therapy (n = 11) were intensively studied by therapeutic intensive seizure analysis (TISA) method. Study phases ran from the baseline phase to the antiepileptic drug (AED) withdrawal phase until the AED free phase, 3 days for each phase. Seizure duration and frequency obviously increased during the withdrawal process in each group (P < 0.05). The duration of secondarily generalized clonic signs markedly increased with the tapering of each drug; tonic signs, however, only in the AED free phase (P < 0.05). The frequency of secondary tonic and clonic signs only increased in the CBZ and CBZ + LTG group. Intergroup comparisons of all variables were insignificant (P > 0.05). There was no change of ictal EEG localization during all withdrawal protocols. All patients experienced more severe seizures during the withdrawal processes. An earlier aggravation of the clonic signs than the tonic signs was observed in each group. Difference between the withdrawal effects of LTG and CBZ monotherapy and LTG + CBZ polytherapy was mainly in the frequency change of ictal signs. The withdrawal process did not influence the ictal EEG localization. This study justified the withdrawal in pre-surgical localization, rationalized precautions for possible accompanying risks, and also aroused attentions in clinical anticonvulsant trials and substitutions involving withdrawal process.     

Clobazam in the treatment of Lennox-Gastaut syndrome

Purpose:   This randomized, double-blind, dose-ranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS).
Methods:   Sixty-eight patients with LGS aged 2–26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study.
Results:   Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of ≥25%, ≥50%, and ≥75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued.
Conclusions:   Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced.     

Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy

Purpose: This study investigated the efficacy and safety of zonisamide (ZNS) adjunctive therapy in children with intractable epilepsy to existing antiepileptic drugs (AEDs). Methods: A clinical retrospective study was performed from 2003 to 2005 at two tertiary epilepsy centers. We reviewed the data from 163 children (107 boys and 56 girls) who experienced more than four seizures per month, whose seizures were intractable to an initial 2 or more AEDs, and could be followed up for at least 6 months after ZNS adjunctive therapy initiation. Efficacy was estimated by seizure reduction rate according to seizure types including infantile spasms, and adverse events were also measured. Results: Seventy-nine patients (48.5%) out of 163 patients experienced a reduction in seizure frequency of more than 50%, and 25 patients (15.3%) became seizure-free. The rate of seizure reduction greater than 50% in children with partial seizures was 40.5% (17/42) and in children with generalized seizures was 51.2% (62/121). Of 36 patients who manifested mainly myoclonic seizures, 20 patients (55.6%) showed a seizure reduction of more than 50% and 9 patients (25.0%) were seizure-free. Mean maintenance dosage of drug was 8.2 mg/kg/day (range 5.0-16.0 mg/kg/day). Adverse events were documented in 15 children (9.2%), including somnolence (8 patients), fatigue, and anorexia, but all were transient and successfully managed. One patient discontinued ZNS therapy due to acute pancreatitis. Conclusion: ZNS adjunctive therapy is an effective and safe treatment in various childhood intractable epilepsy.     

Vigabatrin in adults with poorly-controlled epilepsy and learning disabilities.

Twenty-two adult patients with uncontrolled epilepsy and severe learning difficulties were included in an open study of vigabatrin. Patients were all in residential care and had experienced at least 12 seizures during the previous 12 months despite all attempts to optimize antiepileptic drug (AED) treatment. Following a 4 month baseline period, vigabatrin 500 mg twice daily was added to the current AED treatment and the dose increased according to response, up to a maximum of 4 g/day. Ten patients achieved a reduction in seizure frequency of more than 50% during this 4 month dose titration phase. Two patients had no seizures during the baseline period. For the 30 patients with seizures during the baseline period the median improvement in seizure frequency with the addition of vigabatrin was 49% (P = 0.014). The response rate was higher for patients with partial seizures than for those with generalized seizures. Ten patients continued with vigabatrin while the dose of one of their other AEDs was gradually reduced and successfully withdrawn in three patients. Adverse events were reported in 20 patients during the 64 week study period. The most frequently reported events were sedation (8 patients), aggression (4 patients), agitation (3 patients) and ataxia (3 patients). No patients were withdrawn from the study as a consequence of adverse events. Vigabatrin was therefore an effective add-on therapy in 45% of these difficult-to-treat patients and allowed reduction of other AED treatment in a small number.     

Felbamate: A Clinical Trial for Complex Partial Seizures

We performed a randomized, double-blind, three-period cross-over study of felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate: Carter-Wallace 554) in patients with complex partial seizures. Patients continued carbamazepine (CBZ) throughout the study and were observed in the hospital for the entire trial period. The entry criteria required at least six seizures in a 3-week baseline period (and no more than 1 week with a single seizure) with CBZ alone. Thirty subjects were randomized. Two left the study after randomization, 1 owing to seizure exacerbation, and 1 owing to hyponatremia, which may have been related to CBZ therapy. The daily dosage of 50 mg/kg (maximum 3,000 mg) FBM per day was well tolerated by all 28 patients who completed the study. Only mild adverse experience were observed during the trial. FBM reduced CBZ level (p less than 0.0001; 95% confidence interval -28%, -20%). There was no significant difference in seizure frequency between placebo and FBM periods (one-sided p = 0.172), but when a correction was made for the lower CBZ level noted during FBM periods, the data suggested a strong antiseizure effect of FBM.     

Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate

Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 +/- 0.93 (mean +/- SEM), decreasing to 0.87 +/- 0.71 with addition of FBM, and 0.82 +/- 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced. FBM clearance decreased an additional 16.5%.     

Carbamazepine-exacerbated epilepsy in children and adolescents

Forty-nine children and adolescents whose seizures reportedly worsened while receiving carbamazepine (CBZ) were studied retrospectively. Twenty-six patients met criteria for excellent documentation of carbamazepine-exacerbated seizures. Four epileptic syndromes were particularly affected: childhood absence epilepsy; focal symptomatic, frontal lobe epilepsy; Lennox-Gastaut syndrome; and severe myoclonic epilepsy of infancy. Eight of the 26 patients developed new-onset absence seizures and three patients with established absence epilepsy experienced absence status. Other seizure types, including atonic, tonic-clonic, and myoclonic, developed in eight patients treated with CBZ, and new generalized spike-and-wave discharges were observed in electroencephalograms of nine patients. CBZ is a widely used, effective antiepileptic drug, particularly for partial or partial complex seizures; however, if uncontrolled, generalized seizures occur after CBZ is prescribed for children or adolescents with absence or mixed seizures, a trial of CBZ discontinuation is warranted. The data reported here do not permit calculation of the incidence of this phenomenon.