A Comment on the Efficacy of Valproate in the Treatment of Partial Seizures

Summary: Discrepancies in the findings of studies sponsored by the Department of Veterans Affairs (VA) in the United States and the Medical Research Council (MRC) in the United Kingdom concerning the efficacy of valproate (VPA) in controlling simple or complex partial seizures, particularly those without secondarily generalized seizures, were reviewed. It was noted that the two studies differed with respect to their subjects' pretreatment seizure frequency. The frequency of complex partial seizures before treatment was obviously greater in the VA study, where carbamazepine (CBZ) provided better seizure control than VPA. Based on other comparative and non-comparative studies as well as the author's over 20 years of experience in the use of VPA in a tertiary epilepsy clinic, it is suggested that although VPA may be effective in controlling both the secondarily generalized seizures of symptomatic localization-related epilepsies and the generalized tonic-clonic seizures of idiopathic and. if not always, symptomatic generalized epilepsies, the efficacy of VPA in controlling simple or complex partial seizures is likely limited to patients with infrequent seizures.     

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.     

Gabapentin as Add-on Therapy for Refractory Partial Epilepsy: Results of Five Placebo-Controlled Trials

Summary: Gabapentin (GBP, Neurontin), a new antiepi-leptic drug (AED) with a novel mechanism of action, exhibits low acute toxicity in mice, rats, and monkeys, and is not teratogenic. GBP pharmacokinetics are simple and predictable; GBP is eliminated by urinary excretion, is not protein-bound or metabolized, does not induce or inhibit hepatic enzymes, and does not interact with other AEDs. In five placebo-controlled, double-blind studies of GBP as add-on therapy, 307 patients with refractory partial seizures received placebo and 485 received GBP dosages of 600, 900, 1,200, or 1.800 mg/day for 12 weeks following a 12-week baseline. Seizure frequency, as measured by response ratio and responder rate, was improved for patients receiving GBP compared with placebo; differences were statistically significant in two of the three large, multicenter studies. Adverse events occurred in 76% of GBP-treated patients, compared with 57% of placebo-treated patients. No serious adverse events were consistently attributable to GBP therapy. Changes in clinical laboratory values were not considered clinically important. GBP represents a significant addition to the armamentarium of AEDs available for treatment of patients with 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.     

New Antiepileptic Drugs Already Registered

Summary: Vigabatrin, lamotrigine, and oxcarbazepine are three of the many new antiepileptic drugs (AEDs) already registered in several countries that highlight some of the typical problems and prejudices of new AEDs. Both the therapeutic action and the side-effect profiles of new AEDs are only basically known with marketing. For all three of these new AEDs, antiepileptic effects have been demonstrated beyond doubt, but they still must withstand the test of clinical usefulness in substantial patient numbers. All three have some effect on focal seizures, but their clinical spectrum probably will turn out to be by no means uniform. These three AEDs are, in general, well tolerated, but it would be premature to compare their safety with traditional AEDs as one must be prepared for rare or delayed untoward effects that may be discovered later, as occurred with some older AEDs.     

Tiagabine: A Novel Drug with a GABAergic Mechanism of Action

Summary: The various possibilities for manipulating the γ-aminobutyric acid (GABA) system to augment GABAergic inhibition have been surveyed with reference to the relevant antiepileptic compounds that have been successfully or unsuccessfully investigated in relation to these different mechanisms of action. The first clinical studies of tiagabine (TGB), a novel GABA-uptake inhibitor are now available. These studies utilized a novel design, the enrichment (Amery) design, which is put into perspective compared to classical clinical trial designs. Possible advantages and disadvantages of TGB, as seen at this stage in development, have been identified.     

Introduction: Goals

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABA_A-mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth-ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug-resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow-up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome , or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.     

A Retrospective Study of 113 Epileptic Patients Treated with Sustained-Release Valproate

Summary: A retrospective study of 113 patients treated with a sustained-release form of valproate (SRF-VPA), known as the "chrono" formulation in most European countries, led to the following conclusions: Patients treated with the old VPA formulation could immediately receive the same daily dosage of SRF-VPA without loss of seizure control when administered as a single evening dose. The tolerability of SRF-VPA was good and twice or single daily dosing was preferred by all our patients. Whether or not SRF-VPA should be used as first or second-line treatment in partial seizures that do or do not secondarily generalize is unclear. Our study demonstrates that the efficacy of SRF-VPA is comparable with that of other major antiepileptic drugs such as carbamazepine (CBZ). In refractory seizures, the combination of SRF-VPA and CBZ seemed to be the most satisfactory treatment. Based on these results SRF-VPA is a promising drug for all types of seizures even in low daily dosage, but further clinical work is required to confirm our observations.     

Strategies for the Development of Drugs for Pharmacoresistant Epilepsies

Summary: Presently, most strategies for development of antiepileptic drugs (AEDs) center around seizure models that are known to respond to presently marketed AEDs. These strategies do not take into account that epilepsy can be a progressive disease. Moreover, region-specific aspects of ep-ileptogenesis are rarely considered when new AEDs are developed. Seizures in the temporal lobe are often difficult to treat. Animal studies on various seizure models in the hippocampus and the entorhinal cortex (EC) suggest that these structures do not a priori produce seizures that are difficult to treat. However, seizure-like events in the EC tend to progress to a state of status epilepticus-like activity that cannot be suppressed by presently marketed AEDs. Loss of 7-aminobutyric acid (GABA)ergic neurotransmission and increased excitatory synaptic coupling seem to cooperate for induction of this state. Epilepsy induced alterations in the interaction between the EC and the hippocampus may lead to alterations that facilitate precipitation of seizures. Because of the recurrent interaction between the hippocampus and the EC, these seizures may reach an intensity that is no longer controllable by presently available AEDs. Ontogenetic alterations of the circuitry between the EC and the hippocampus. seizure-induced stabilization of synaptic connections over-expressed during ontogenesis, seizure-induced lesions and subsequent rearrangements of internal cell properties, and synaptic arrangements and kindling-like alterations of nerve cell and glial behavior may all be involved in the generation of a neuronal aggregate whose balance between inhibitory and excitatory processes becomes readily disturbed. Strategies for the development of AEDs treating such seizures should suppress hyperactivity and prevent progression of epilepto-genesis. AEDs directed against seizures may be effective if they can be given in sufficient concentrations to suppress very intense local seizures.     

Clobazam for Treatment of Intractable Epilepsy: A Critical Assessment

Summary: Clobazam (CLB), a 1,5-benzodiazepine, is a remarkably effective add-on drug for individual patients with refractory partial epilepsy. CLB has an excellent safety record. As with all benzodiazepines used for treating epilepsy, sedation and withdrawal effects, together with the development of tolerance, limit its usefulness. Recent efforts to prevent or reverse tolerance with intermittent administration of CLB or periodic injection of a benzodiazepine antagonist, flumazenil, are encouraging and justify further investigations.     

Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double-Blind, Placebo-Controlled Trials

Summary: A pooled analysis of data from five similarly designed double-blind, placebo-controlled trials of topiramate (TPM) as add-on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200-1,000 mg daily and 174 who received placebo. In the intent-to-treat pooled analysis, TPM was significantly ( p ≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly ( p ≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly ( p ≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.     

Lamotrigine: A Review of Antiepileptic Efficacy

Summary: Lamotrigine (LTG) is a chemically novel anti-epileptic drug (AED) that blocks voltage-sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single-dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double-blind, placebo-controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox-Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.     

Tiagabine

Summary: Tiagabine (TGB), a specific γ-aminobutyric acid (GABA)-uptake inhibitor, is a potential new antiepileptic drug with a novel mechanism of action. In animal models of epilepsy as well as in a placebo-controlled trial in patients with complex partial seizures, TGB showed significant anticonvulsant effects. TGB was well tolerated by most patients.     

Lamotrigine Versus Other Antiepileptic Drugs: A Star Rating System Is Born

Summary: With the launching worldwide of a range of new antiepileptic drugs (AEDs), the prescriber has a much wider choice than ever before. Comparative studies between new and established AEDs are few, and those between new AEDs are rarely performed. This report considers the strengths and weaknesses of nine new and established AEDs. Scores ranging from -2 to +2 are given under six headings: mechanism of action, pharmacokinetics, efficacy, side effects, drug interactions, and a comfort factor. Perceived advantages and disadvantages in their clinical use are summarized and a final "star rating" produced for each. This process is illustrated by a detailed critique of lamotrigine (LTG). The star system is intended to stimulate dialogue among epileptologists in reaching a consensus in the pharmacologic management of the epileptic patient.     

Controlled and Comparative Trials with Valproate: United States

Valproic acid (VPA) was released for general use in the United States in 1978. Since that time the use of VPA has steadily grown, and considerable literature on valproate from the United States has resulted. Despite this fact, however, very few studies that were either well controlled or compared the efficacy of VPA with that of another standard anticonvulsant drug have been published from this country.     

Clinical Development Outlook of Oxcarbazepine

Summary: Oxcarbazepine (OCBZ) has been accepted for registration as a first-line antiepileptic drug (AED) in several countries. However, because of changing regulations, further studies confirming statistically significant proof of efficacy are necessary in accordance with new standards. Therefore, Ciba has initiated a worldwide clinical development program to achieve registration. Four different types of design to demonstrate statistically significant proof of efficacy in partial seizures will be initiated. These studies are a "classical" poly-therapy add-on study, a monotherapy substitution trial, a high-dose/low-dose active-control monotherapy study, and a study in presurgical patients.
Anticonvulsants     

Preliminary Open-Label Experience with Topiramate in Primary Generalized Seizures

Summary: Preliminary data concerning the effectiveness of topiramate (TPM) in the management of resistant primary generalized seizures were obtained from the open-label extension of a double-blind, placebo-controlled trial of TPM. The controlled trial enrolled patients experiencing three or more primary generalized tonic-clonic seizures (PGTCS) during an 8-week baseline period. Twelve of 13 patients who completed double-blind treatment elected to receive extended open therapy with TPM and were followed for periods ranging from 2 to 11 months. Of the 12 patients, 11 (92%) experienced a 50% or greater reduction in tonic-clonic seizures during their last 2 months of open-label TPM therapy compared to their pre-double-blind baseline period, and 7 (58%) were seizure-free during the open extension. Of five patients reporting absence seizures at baseline, four (80%) demonstrated a 50% or greater reduction in seizures. In seven of the 12 patients, a concomitant antiepileptic drug (AED) was discontinued or its dosage was reduced during open TPM treatment. The most common adverse events observed in the open study extension were weight reduction (five patients), weight increase (two patients), and drowsiness (two patients). The results of controlled trials are needed to determine the efficacy of TPM in primary generalized seizures. However, these preliminary findings are encouraging.     

Clobazam in the Treatment of Epilepsy: A Review of the Literature

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short-term and long-term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long-term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short-term add-on therapy; but it should also be tried as long-term therapy in some situations, especially as add-on therapy for patients with refractory epilepsy, as add-on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.     

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.     

Clinical Experience with Oxcarbazepine

Summary: Controlled studies of oxcarbazepine (OCBZ) and the largest of the open studies of OCBZ were reviewed. The overall results indicated that OCBZ has the same clinical effect as carbamazepine (CBZ) but causes fewer adverse effects. Studies of allergic toxicity seem to indicate that OCBZ may be tolerated in the majority of patients developing allergy towards CBZ. We concluded that OCBZ is a drug of first choice for the treatment of epilepsy.