A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. [Efficacy of sodium valproate in partial epilepsy. Crossed study of valproate and carbamazepine]. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group.
The long-term efficacy and adverse-event profiles of sodium valproate and carbamazepine in children with newly diagnosed primary generalised or partial epilepsy were compared at 63 outpatient clinics. Children with two or more generalised tonic-clonic or partial seizures in the previous six months were randomised to oral sodium valproate (N = 130) or oral carbamazepine (N = 130) and followed for three years as outpatients. Dosages were increased as needed until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine were equally effective in achieving high levels of seizure control in both primary generalised seizures and partial seizures with or without generalisation. Adverse events were mostly mild, few necessitating drug withdrawal. Those particularly associated with valproate were weight increase, alopecia and appetite increase, and with carbamazepine, rashes, somnolence, diplopia and abnormal gait/ataxia. An open response-conditional cross-over study of valproate versus carbamazepine has been done in previously untreated patients with partial seizures. Thirty-one patients entered the study. Nineteen were followed up to one year. It appeared that valproate was at least as effective as carbamazepine: at one year, 11 patients were seizure-free on valproate and only 8 were seizure-free on carbamazepine. Furthermore no side-effect was noted in valproate therapy, whereas carbamazepine was stopped in 2 patients because of skin rashes. The efficacy of sodium valproate in partial epilepsy remains controversial. It is of course limited when given as co-therapy in severe epilepsies, uncontrolled with other major antiepileptic drugs. However in naive patients, with recent and previously untreated partial epilepsies, a one-drug treatment with valproate appears to be as effective as carbamazepine or phenytoin. It has less unwanted side-effects and should be prescribed as first line treatment. The long-term efficacy and safety of sodium valproate and carbamazepine in adult outpatients with newly diagnosed primary generalised or partial and secondarily generalised seizures were compared in a randomised, open, multicentre study at 22 neurology outpatient clinics. Patients were randomised to oral sodium valproate (Epilim EC enteric coated 200 mg tablets twice daily, n = 149) or oral carbamazepine (100 mg twice daily increasing to 200 mg twice daily in week 2, n = 151) and followed up for three years. If clinically necessary, dosages were regularly increased until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine controlled both primary generalised and partial seizures equally effectively overall. Significantly more patients on sodium valproate than carbamazepine (126/140 (90%) v 105/141 (75%), p = 0.001) remained on randomised treatment for at least six months. Skin rashes occurred significantly more often in carbamazepine recipients than in sodium valproate recipients (11.2% v 1.7%, p < 0.05) and carbamazepine was associated with a higher withdrawal rate because of adverse events (15% v 5% on sodium valproate) in the first six months of treatment. There was no difference between the drugs in the rate of withdrawal because of poor seizure control at any stage, regardless of seizure type. At the end of the three year trial period, over 70% of the available patients were still on randomised treatment or had recently stopped treatment after achieving full seizure control. Sodium valproate and carbamazepine were both associated with a high degree of overall seizure control regardless of seizure type and both have good long-term tolerability in adult patients with newly diagnosed epilepsy. Recommendations are made for a higher initial dosage regime for sodium valproate in partial seizures. Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin.
                We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred.
                For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001).
                Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects. Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs. The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients. We know of only one randomised comparative trial (of two drugs) in newly diagnosed childhood epilepsy. We have undertaken a long-term, prospective, randomised, unmasked, pragmatic trial of the comparative efficacy and toxicity of four standard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy.
                Between 1981 and 1987, 167 children aged 3-16 years, who had had at least two previously untreated tonic-clonic or partial seizures, with or without secondary generalisation, were randomly allocated treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform to standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission.
                The overall outcome with all four drugs was good. 20% of children remained free of seizures and 73% had achieved 1-year remission by 3 years of follow-up. We found no significant differences between the drugs for either measure of efficacy at 1, 2, or 3 years of follow-up. The overall frequency of unacceptable side-effects necessitating withdrawal of the randomised drug was 9%. This total included six of the first ten children assigned phenobarbitone; no further children were allocated this drug. Of the other three drugs, phenytoin (9%) was more likely to be withdrawn than carbamazepine (4%) or sodium valproate (4%). INTERPRETATION Our data will inform choice of drug and outcome with four of the standard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children. One hundred and eighty one patients with previously untreated epilepsy were randomised to sodium valproate, phenytoin or carbamazepine as monotherapy and followed up for a median period which ranged from 14 to 24 months. All three drugs were highly effective in the control of generalised seizures but less effective for partial seizures. Excellent or good control was achieved with therapeutic levels of sodium valproate and carbamazepine, but with subtherapeutic levels of phenytoin. Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated. Vigabatrin is a newly licensed drug for use in patients with epilepsy. We investigated whether this drug was comparable to standard first-line monotherapy in efficacy and incidence of adverse events.
                We enrolled 459 patients with newly diagnosed, previously untreated partial epileptic seizures from 44 European centres and randomly assigned them carbamazepine 600 mg daily (n=230) or vigabatrin 2 g daily (n=229). After initial maintenance doses were reached, doses were adjusted downwards (in the case of adverse events) or upwards (in the case of seizures) by the clinician. The primary outcome was time to withdrawal because of lack of efficacy or adverse events. Secondary outcomes included efficacy (time to 6-month remission of seizures, time to first seizure after initial dose stabilisation), and adverse events (incidence and severity). Analysis was by intention to treat.
                Time to withdrawal for lack of efficacy or adverse events did not differ between groups (p=0.318). Vigabatrin was better tolerated than carbamazepine with fewer withdrawals, but was more frequently associated with psychiatric symptoms (58 [25%] vs 34 [15%]) and weight gain (25 [11%] vs 12 [5%]). Carbamazepine was associated with rash (22 [10%] vs seven [3%]). All efficacy outcomes favoured carbamazepine and failed to show equivalence between the two drugs. No significant difference was found for time to achieve 6 months of remission from seizures (p=0.058), but the most powerful outcome, time to first seizure after the first 6 weeks from randomisation, showed carbamazepine to be significantly more effective than vigabatrin (p=0.0001).
                Vigabatrin seems less effective but better tolerated than carbamazepine, which is the first-choice drug for the treatment of partial epilepsies. Vigabatrin cannot therefore be recommended as a first-line drug for monotherapy in this group of patients.
We have found some evidence to support the policy of using carbamazepine as the first treatment of choice in partial epilepsies, but no evidence to support the choice of valproate in generalized epilepsies, but confidence intervals are too wide to confirm equivalence. Misclassification of people with epilepsy may have confounded our results, and has important implications for the design and conduct of future trials.