Lennart Gram

Antiepileptic drugs as a cause of worsening seizures

Summary: Purpose: Although the paradoxical ability of anti‐epileptic drugs (AEDs) to increase seizure activity has been recognized for decades, the underlying mechanisms are poorly understood and few systematic studies have addressed this problem. This article is intended to provide a critical review of available literature on this topic.

Sodium Valproate, Serum Level and Clinical Effect in Epilepsy: A Controlled Study

Summary: Clinical effects at three different serum levels of sodium valproate (VPA) were compared in a triple‐blind, multiple crossover trial comprising 13 epileptic inpatients. Patients were selected regardless of seizure type, and all were in concomitant antiepileptic treatment, which was kept constant throughout the study. A significant relationship between the decrease in number of seizures and increasing VPA serum level was demonstrated. The relationship between VPA dose and serum level was curvilinear. Statistical evaluation of patients by seizure type in relation to clinical effect of VPA was only possible for secondary generalized seizures. Between phenytoin, phenobarbital, and carbamazepine and the different VPA serum levels no interactions could be demonstrated. Recorded side effects were always mild and transient. No obvious correlation between side effects and VPA serum level was established.

Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons.

Valproate (VPA) and vigabatrin (gamma-vinyl GABA, GVG) are two novel antiepileptic drugs with a presumed GABAergic mechanism of action. However, for VPA, this aspect has been extensively debated. The aim of the present study was to investigate whether treatment of cultured neurons with clinically relevant concentrations of VPA and GVG might enhance release of endogenous GABA. In order to address the question of the fate of released GABA, studies involving exogenous, radiolabeled GABA were also undertaken. Exposure of neurons to GVG in a concentration range of 10-300 microM led to a significant increase in the cellular GABA content, whereas concentrations of VPA of 30-300 microM had no such effect. Treatment of the neurons with concentrations of GVG as low as 25 microM resulted in a pronounced increase in evoked release of endogenous GABA, compared to controls. Only high concentrations of VPA (300 microM) caused an increase in the synaptic GABA release, which reached statistical significance. Preincubating the neurons with exogenously labeled GABA in the presence of GVG or aminooxyacetic acid, both of which block GABA metabolism, caused a decrease in the specific radioactivity in the cellular GABA pool. This, together with the observation that the specific radioactivity of the releasable GABA pool always exceeded that of the cellular pool, indicates that exogenously supplied GABA preferentially labels the transmitter pool of GABA.

Newer anticonvulsants: Comparative review of drug interactions and adverse effects

The tolerability and drug interaction profiles of 6 new anticonvulsants: oxcarbazepine, vigabatrin, lamotrigine, gabapentin, tiagabine and topiramate, are reviewed. In general, these new anticonvulsants are well tolerated and drug interaction problems are minor with the exception of the risk of failure of oral contraceptives during treatment with oxcarbazepine or topiramate.In this review, the clinical implications of the tolerability of these drugs are discussed for different patient groups. The choice of which new anticonvulsant for which patient depends upon individual factors, in particular, seizure type, tolerability and practical administration factors.Treating elderly patients may be complicated by an increased sensitivity to adverse effects as these patients very often receive polytherapy for accompanying diseases. Drugs with very simple pharmacokinetic properties may be preferred in this group. Women of childbearing age face specific problems related to the epilepsy and to treatment with anticonvulsants. These include impaired fertility, failure of oral contraceptives and the risk of birth defects. Some new anticonvulsants may be suggested in preference to classical drugs to avoid these problems, but the human experience with newer anticonvulsants is still limited and, therefore, so is knowledge of the risk of congenital malformations in the offspring of mothers taking anticonvulsants. Psychiatric and behavioural changes frequently complicate treatment of patients with mental retardation. Some of the new anticonvulsants, in particular those affecting the γ-aminobutyric acid (GAB A) system such as vigabatrin, seem to exacerbate this problem and should be used with caution in these patients.

Gamma-vinyl-GABA: A single-blind trial in patients with epilepsy

ABSTRACT The anti‐epileptic effect of gamma‐vinyl‐GABA (GVG) was studied using a placebo‐controlled, single‐blind design in 15 patients with therapy‐resistant epilepsy, the majority experiencing complex partial seizures. GVG was added to concomitant treatment, which was kept at constant serum levels. Following administration of 1 g, 2 g and 3 g per day, significant reductions in seizure frequency were observed. A poor correlation was found between GVG serum levels and clinical effect. Only mild and transient side‐effects were observed.

Monotherapy versus Polytherapy in Epilepsy

SummaryIn approximately 70% of patients with newly diagnosed epilepsy, initial treatment with a single antiepileptic drug leads to complete seizure control without intolerable adverse effects. Unfortunately, monotherapy fails, even at maximal tolerated doses, in an important minority of patients. These patients usually have symptomatic epilepsies. For patients with refractory seizures, alternative monotherapy with a second-line agent is a very effective and well tolerated treatment policy. Approximately 40% of patients with partial epilepsy that is refractory to one agent will benefit from alternative monotherapy.If alternative monotherapy fails, polytherapy with a combination of 2 drugs may be helpful in a small minority of patients. However, this efficacy is usually at the expense of added toxicity unless the daily dose of the first drug is reduced. When 3 antiepileptic drugs fail either in sequential monotherapy or combination therapy, diagnostic re-evaluation is required. If surgery is not suitable, monotherapy with the individually best tolerated drug at the lowest effective dose is recommended until more effective antiepileptic drugs become available.

Valproate sodium: a controlled clinical trial including monitoring of drug levels.

The antiepileptic effect of valproate sodium (VPA) versus that of placebo has been evaluated in a controlled clinical trial (double‐blind, crossover type). The concentration of VPA and that of other antiepileptic drugs in serum, as well as findings by EEG, were recorded in the course of the trial.

Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate

Studies investigating the influence of antiepileptic drugs on thyroid hormones usually have compared patients chronically treated with antiepileptic drugs to controls.

Valproate: an updated review

ABSTRACT – Valproate in all its aspects is comprehensively surveyed. Previous reviews covering various aspects such as mechanism of action, clinical pharmacology, clinical efficacy in epilepsy, febrile convulsions and other neurological disorders, side effects, teratogenicity and intoxications are discussed and updated (161 references).

Adjunctive treatment of partial seizures with tiagabine: A placebo-controlled trial

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.