Felbamate Monotherapy: Implications for Antiepileptic Drug Development

Summary: We studied the effect of felbamate (FBM) monotherapy on seizure rate in patients with partial and secondarily generalized seizures undergoing presurgical monitoring at a single site. The study design was a double-blind placebo-controlled parallel monotherapy trial. Forty patients whose seizures had not been controlled by standard antiepileptic drugs (AEDs) were randomized. Seizure type was confirmed by video-EEG monitoring. All baseline AEDs were discontinued, and patients were drug-free for 5.3 ± 2.4 days before randomization to FBM or placebo. After a 4-day titration, seizures were counted for 14 days. Patients receiving FBM had significantly lower seizure rates, whether all randomized patients, patients who survived titration, or study completers were compared. Eight of 19 placebo patients randomized to placebo, as compared with 13 of 21 receiving FBM, completed the 18-day study. Two FBM patients dropped out due to seizures, and 6 dropped out due to side effects, including anxiety, difficulty sleeping, abdominal discomfort, acute psychosis, and orobuccal dyskinesias. Ten placebo patients met the criteria for premature discontinuation owing to seizures, and 1 had an episode of panic. There was no evidence of hepatic or hematologic toxicity. FBM reduces seizure frequency in patients with localization-related epilepsy.     

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.     

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.     

Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study

PURPOSE: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure. METHODS: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months. RESULTS: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences. CONCLUSIONS: No differences were found in overall neurotoxicity between monotherapy and polytherapy.     

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.     

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.     

Associations Between Risk Factors for Valproate Hepatotoxicity and Altered Valproate Metabolism

The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites [2-en-VPA (2-en), 3-en-VPA (3-en) and 4-en-VPA (4-en)] were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4-en/VPA ratio. In the same group, the 4-en/VPA ratio showed a significant positive correlation with serum VPA level, while 3-en/VPA and 2-en/VPA ratios showed significant negative correlations. In patients greater than 10 years, the 4-en/VPA ratio was significantly higher, while the 2-en/VPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4-en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta-oxidative metabolism of VPA to 2-en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA-induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.     

Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy.

The recommended treatment for juvenile myoclonic epilepsy (JME) is valproate (VPA). Recently, topiramate and lamotrigine have also been shown to be effective. The objective of this study was to evaluate the efficacy and tolerability of zonisamide (ZNS) in the treatment of JME. We retrospectively analyzed the records of 15 patients (three M, 12 F, ages 11-20 years) diagnosed with JME at our institution during 2001-2003, and treated with ZNS. Generalized tonic-clonic (GTC), myoclonic and absence seizure response was assessed. The ZNS dose range was 200-500 mg/day (2.0-8.5 mg/kg/day). ZNS was started as the first drug, and as monotherapy, in 13 and was added to VPA in two patients. Follow-up range was 2-24 months (mean 12 months). Overall, 80% of patients on ZNS monotherapy showed good control (> or = 50% seizure reduction). Sixty-nine, 62 and 38% of patients were free of GTC, myoclonic, and absence seizures, respectively. Seizure control was achieved within four to eight weeks of attaining the maintenance dose. One patient on polytherapy had a 75% reduction in seizure frequency, whereas the other patient showed no response. There were no ZNS-VPA interactions. One patient stopped ZNS and was switched to VPA because of poor seizure control. Three patients (20%) experienced side effects (weight loss, headache, dizziness) during escalation, which resolved during maintenance. In this open-label, retrospective study, ZNS was shown to be an effective and well-tolerated drug in the treatment of patients with JME. The ease of titration, good safety profile, once-a-day dosing, lack of significant drug interaction, and short latency for onset of efficacy make ZNS an attractive therapeutic alternative for the treatment of JME.     

The effect of antiepileptic drug therapy on antioxidant enzyme activity and serum lipid peroxidation in young patients with epilepsy

Changes in antioxidant defense mechanisms and the resulting increased lipid peroxidation are involved in the pathogenesis of epilepsy. Research findings concerning the effect of antiepileptic therapies on these processes are discordant. The aim of our study was to estimate, firstly, the activity of the following antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-R), and secondly, malondialdehyde (MDA) serum concentration in children and adolescents newly diagnosed with epilepsy and receiving either carbamazepine (CBZ) or valproate (VPA) monotherapy, or polytherapy. The study group included 90 young patients with epilepsy, aged 6 months to 20 years. In 22 patients epilepsy was newly diagnosed; CBZ monotherapy was administered to 16 patients, VPA monotherapy--to 25, and polytherapy--in 27 cases. The control group consisted of 61 non-epileptic patients aged 4-17 years. SOD, GSH-Px and GSSG-R activities and MDA concentration were measured using spectrophotometry. SOD activity was decreased in newly diagnosed epileptic children receiving VPA or CBZ monotherapy (p < 0.05), or polytherapy (p < 0.01) in comparison to relevant levels in non-epileptic patients. GSH-Px activity was increased in all the patients, but significantly in those receiving polytherapy (p < 0.05). While in patients newly diagnosed with epilepsy no change in GSSG-R activity was found, its level was slightly lower both in those receiving VPA monotherapy and polytherapy, but increased in those with CBZ monotherapy. MDA concentration was elevated in all the epileptic patients, significantly (p < 0.05) both in VPA monotherapy and in polytherapy, while insignificantly--in newly diagnosed epilepsy and in CBZ monotherapy. Our results indicate that in the serum of children and adolescents with epilepsy the oxidants-antioxidants balance is modified by antiepileptic therapy.     

Antiepileptic Drug Treatment After Temporal Lobe Epilepsy Surgery: A Randomized Study Comparing Carbamazepine and Polytherapy

Temporal lobectomy is an effective treatment in selected patients with medically intractable temporal lobe epilepsy (TLE). Postoperative antiepileptic drug (AED) treatment guidelines have not been established, and patients are often treated with polytherapy postoperatively. We prospectively randomized 40 patients undergoing temporal lobectomy to monotherapy with carbamazepine (CBZ, 20) or to continuation of their presurgical polytherapy (20) to assess the efficacy and safety of each regimen during the first year after operation. No significant differences between groups were noted with respect to seizure recurrence rate and type or time of recurrence. Patients in the polytherapy group had a 30% incidence of drug-related side effects as compared with only 10% in the CBZ group. These results suggest that after temporal lobectomy for intractable epilepsy, patients can be safely treated with CBZ monotherapy and that treatment with multiple AEDs is not necessary.     

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.     

Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes

PURPOSE: Compulsory generic substitution of antiepileptic drugs (AEDs) may lead to adverse effects in epilepsy patients because of seizure recurrence or increased toxicity. The study objectives were (a) to quantify and compare the switchback rates from generic to brand-name AEDs versus non-AEDs, and (b) to assess clinical implications of switching from branded Lamictal to generic lamotrigine (LTG) and whether signals exist suggesting outcome worsening. METHODS: By using a public-payer pharmacy-claims database from Ontario, Canada, switchback rates from generic to branded AEDs [Lamictal, Frisium (clobazam; CLB), and Depakene (VPA; divalproex)] were calculated and compared with non-AED long-term therapies, antihyperlipidemics and antidepressants, in January 2002 through March 2006. We then assessed pharmacy utilization and AED dosage among LTG patients switching back to branded Lamictal compared with those staying on generic formulation. RESULTS: The 1,354 patients (403 monotherapy, 951 polytherapy) were prescribed generic LTG, of whom 12.9% switched back to Lamictal (11.7% monotherapy, 13.4% polytherapy). Switchback rates of other AEDs were approximately 20% for CLB and VPA. The switchback rates for AEDs were substantially higher than for non-AEDs (1.5-2.9%). Significant increases in LTG doses were observed after generic substitution for those who did not switch back (6.2%; p<0.0001). The average number of codispensed AEDs and non-AED drugs significantly increased (p<0.0001) after LTG generic entry, especially in the generic group. CONCLUSIONS: These results reflect poor acceptance of switching AEDs to generic compounds. They may also indicate increased toxicity and/or loss of seizure control associated with generic AED use.     

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.     

Treatment guidelines for adult epilepsy]

We reviewed the treatment strategies and choices of drugs for adult patients with epilepsy. As evidence from controlled studies for the older drugs is scarcely available from the literature, we added a clinical study performed in our hospital and an expert consensus study. Published randomized clinical studies revealed carbamazepine (CBZ) to be the treatment of choice, but provided little evidence for the differences in efficacy between phenytoin (PHT), valproate (VPA), phenobarbital (PB) and zonisamide (ZNS). The clinical study in our patients with intractable localization-related epilepsy indicated the superior efficacy of CBZ and PHT over VPA or ZNS. Sixty-nine experts converged on the opinion that monotherapy should be started with VPA for seizures of both idiopathic and symptomatic generalized epilepsy, and with CBZ for seizures of localization-related epilepsy. When the trials with 2-3 monotherapy failed, surgery should be considered for localization-related epilepsy. We proposed practical guidelines for treatment of patients with adult epilepsy, including rehabilitation and care for improvement of quality of life.     

Efficacy and tolerability of antiepileptic drugs in an Omani epileptic population

OBJECTIVE: The aim of this hospital-based study is to get an insight into the efficacy and tolerability of antiepileptic drugs (AED) in Omani epileptic patients. PATIENTS AND METHODS: All Omani patients (aged 14 years and above) suffering from epileptic seizures for at least 2 years and followed-up by board-certified neurologists in Sultan Qaboos University Hospital (SQUH) were evaluated. The treatment retention rate since first visit at SQUH and over the last 2 years was used as primary efficacy measure of AED therapy. Change in seizure-frequency and side effect profiles were also assessed. RESULTS: In this population of 203 confirmed epileptic patients, generalized tonic-clonic (40%) and partial seizures (39%) were most commonly observed, idiopathic/cryptogenic origin (81%) being the most frequent encountered origin. Sixty one percent of the patients were controlled with an AED in monotherapy and overall 34% of patients could be successfully maintained on monotherapy during the whole follow-up period at SQUH (median 6 years). The treatment retention rates for carbamazepine (CBZ) at a daily dose of 400-600 mg, sodium valproate (VPA) at a daily dose of 500-1000 mg, and phenytoin (PHT) at a daily dose of 300 mg, in monotherapy over the total follow-up period was 51, 50, and 21%, respectively. In contrast, over the last 2 years these rates were highest for VPA (91%) followed by CBZ (83%) and PHT (73%). Adverse drug reactions were recorded in 67% of patients, and were most commonly encountered with VPA. CONCLUSIONS: Despite a higher adverse effect profile for VPA, long-term treatment with CBZ and VPA appeared to be equally effective in terms of treatment retention rates and seizure control.     

Topiramate: uses in people with an intellectual disability who have epilepsy

The novel anticonvulsant topiramate has been shown to have efficacy across a range of seizure types including both generalized and partial seizures in several well-designed randomized controlled trials. It has also been shown to be effective in atonic seizures associated with Lennox-Gastaut syndrome. Tolerability data show a tendency to neuropsychiatric side-effects, such as confusion and word finding difficulties, when topiramate is used in polytherapy; these side-effects are reduced in monotherapy usage. The efficacy and spectrum of seizures treated by topiramate suggests that it has an important role in managing epilepsy in people with intellectual disability. The predictable side-effects can be monitored in clinical practice and possibly reduced by slow dose increments. The data set of patients with intellectual disability is still too small to rule out idiosyncratic drug reaction.     

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.     

Valproate Monotherapy in 30 Patients with Partial Seizures

This retrospective pilot study describes 30 patients diagnosed and treated for complex partial seizures (CPS) and simple partial seizures (SPS) with and without generalization who received valproate (VPA) monotherapy after lack of response or allergic reaction for carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB). Seizures were tabulated daily on seizure calendars by the patients. Three time periods were examined for seizure frequency, 90 days before VPA treatment and 90 and 180 days after VPA treatment. Twenty-two were "controlled" or "improved" (reduction of seizure activity by greater than or equal to 51%) 6 months following the initiation of VPA. VPA was particularly effective in 17 patients who had secondarily generalized tonic-clonic seizures (GTCS) as a subtype of partial seizures. Failure of response to VPA in eight patients appears to be related to their type of partial seizure (SPS or CPS alone, without GTCS) and duration of uncontrolled recurrent seizures. Etiology and compliance were not related to treatment failure. This study supports the need for a double-blind controlled trial with VPA in patients with partial seizures.