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The current limitations of antiepileptic drug (AED) therapy were the topic of a discussion group meeting at the 5th European Congress on Epileptology, Madrid, 6-10 October 2002. This review contains four short papers covering the topics discussed by the speakers at this meeting and an account of the ensuing discussion with all participants. The meeting focused on four issues. (i) Are mechanisms of action of AEDs useful to predict treatment outcome? The short answer to this question was no, for several reasons. These include the fact that clinically relevant mechanisms in individual patients remain unclear, the treatment of epilepsy targets the symptoms rather than the cause of the disease, and that current seizure classification defines heterogeneous patient populations. (ii) The benefits of the often recommended titration of the dose to the maximum tolerated level when seizures persist at average AED doses. A re-evaluation of this practice showed that dose escalation achieves seizure freedom in only 1 of 4 patients with newly diagnosed epilepsy and only 1 of 10 patients with refractory epilepsy are likely to experience a greater than 50% reduction in seizure frequency. Being aware of the limited utility of maximum dose titration and subsequent dose reduction if no significant individual benefit is achieved avoids medical over-treatment with a worsening risk-benefit balance. (iii) When single drug therapy is not sufficiently effective, adding a second drug or alternative monotherapy are common options. Based on published data, there is no conclusive evidence in favour of either alternative monotherapy or second-line polytherapy. A pragmatic choice may be to evaluate the combination and then attempt to withdraw the first drug in the case of success. This may prevent the substitution of a partially efficacious drug by a non-efficacious drug. The choice of the second drug should, in theory, be based on which first drug has failed but again compelling evidence to support specific recommendations is lacking. (iv) Unexpected worsening of seizures may occur in many circumstances and has many causes, including tolerance and adverse pharmacodynamic effects of individual AEDs on seizure generating mechanisms. Patients are usually aware of aggravation and may express a "dislike" for a particular AED as a warning sign for physicians to modify the medication. The availability of numerous AEDs, particularly with single mechanisms of action, has increased the risk of paradoxical effects that may go undetected in clinical trials and only surface during astute clinical observations.

After a hiatus of almost 20 years, nine new antiepileptic drugs were licensed during the last decade of the 20th century. Expansion of the range of drug treatments for epilepsy complicates selection of the most suitable drug, or combination of drugs, for individual patients. Clinical experience suggests that mechanism of action may become an important criterion in this decision-making process. At the cellular level, three major pharmacological actions are recognised: modulation of voltage-dependent ion channels, enhancement of inhibitory neurotransmission, and attenuation of excitatory transmission. This review provides an update on the principal mechanisms of action of a range of established and modern antiepileptic drugs.

Background: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with gamma-aminobutyric acid (GABA)-related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye., Methods: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined., Results: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain., Conclusions: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.

In the past decade, nine new drugs have been licensed for the treatment of epilepsy. With limited clinical experience of these agents, the mechanisms of action of antiepileptic drugs may be an important criterion in the selection of the most suitable treatment regimens for individual patients. At the cellular level, three basic mechanisms are recognised: modulation of voltage-dependent ion channels, enhancement of inhibitory neurotransmission, and attenuation of excitatory transmission. In this review, we will attempt to introduce the concepts of ion channel and neurotransmitter modulation and, thereafter, group currently used antiepileptic drugs according to their principal mechanisms of action.

The novel antiepileptic drug, retigabine, has been reported to have multiple mechanisms of action, including potentiation of gamma -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered retigabine either as a single dose or daily for 5 days. At 4 h after dosing, brains were removed and analysed for GABA, glutamate, and glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of retigabine significantly lowered brain concentrations of glutamate and glutamine. Repeated treatment significantly reduced the activity of GABA-transaminase. The drug was essentially without effect on all other parameters investigated. These results suggest that retigabine blocks GABA metabolism rather than enhancing GABA synthesis. In addition, the drug may also lower brain concentrations of the excitatory neurotransmitter glutamate and its precursor, glutamine. These effects may contribute to the antiepileptic action of retigabine., (Copyright 2000 Academic Press.)

Purpose: This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic., Methods: One hundred seventy patients (82 men, 88 women, aged 18-75 years) with refractory localization-related (n = 134) or idiopathic generalized epilepsy (n = 36) were started on adjunctive TPM using a standard titration schedule. TPM was introduced after a 3-month prospective baseline, and doses were adjusted according to clinical response. End points were seizure freedom for 6 months, > or =50% seizure reduction for 6 months compared with baseline at the highest tolerated TPM dose (responder), or discontinuation of TPM because of side effects, lack of efficacy, or both., Results: Thirty-nine (23%) patients were seizure-free, and 80 (47%) more patients had a useful therapeutic response. Thirteen seizure-free patients and 16 responders took 100 mg of TPM daily or less. TPM was discontinued in 51 (30%) patients. The most common side effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Concomitant antiepileptic drugs (AEDs) were stopped in 30 patients. Twelve were established on TPM monotherapy, eight of whom remained seizure-free. Final TPM doses and concentrations varied widely among the three outcome groups., Conclusions: TPM was efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use. A good response was obtained in many patients with TPM doses substantially lower than those studied in regulatory clinical trials. The wide variation in dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.

Purpose: Topiramate (TPM) is a new antiepileptic agent with a multifactorial mechanism of action. The drug potentiates responses to gamma-aminobutyric acid (GABA) at the GABA(A) receptor and has inhibitory effects on neuronal sodium channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase. Recent evidence has, however, suggested that the drug also increases brain GABA concentrations in humans. These studies were designed to investigate the neurochemical basis of this observation., Methods: Adult male mice were randomised into two groups and administered TPM (0-1,000 mg/kg) intraperitoneally either as a single dose or daily for 8 days. At 4 h after the final dose, brain tissues were analysed for concentrations of GABA, glutamate, and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. TPM levels in brain also were determined., Results: Single-dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the brain at doses of > or =10 mg/kg., Conclusions: These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug.

In light of theirclosely related mechanisms of action, and preliminary clinical evidence suggesting that they possess similar efficacies, it has been anecdotally suggested that vigabatrin and tiagabine may prove to be therapeutically indistinguishable. As a result, we have conducted a preclinical comparison of their anticonvulsant profile and mechanism of action. Pentylenetetrazol and maximal electroshock seizures were employed to determine the experimental anticonvulsant profile. Mechanisms of action were investigated using assays of gamma -aminobutyric acid (GABA), GABA-transaminase and glutamic acid decarboxylase in mouse brain and GABA uptake and GABA-transaminase in rat astrocyte cultures. Vigabatrin was without effect on either pentylenetetrazol- or maximal electroshock-induced seizures, whereas tiagabine increased the latency to pentylenetetrazol seizures and reduced the incidence of maximal electroshock seizures. In mouse brain assays, tiagabine was without effect, while vigabatrin increased GABA concentrations and reduced GABA-transaminase and glutamic acid decarboxylase activities. In cortical astrocyte cultures, vigabatrin reduced the activities of both GABA uptake and GABA-transaminase, whereas tiagabine blocked GABA uptake alone. These results suggest that vigabatrin and tiagabine have differing efficacy in experimental seizure models and distinct neurochemical effects. It is possible, then, that these drugs will have different spectra of activity and toxicity profiles in human epilepsy., (Copyright 1999 BEA Trading Ltd.)

The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.

This case-controlled study explored the relationship between bone mineral density (BMD) and long-term treatment with antiepileptic drugs (AEDs) in older adults with epilepsy. Seventy-eight patients (47 post-menopausal females, 31 males, aged 47-76 years) with epilepsy participated in the study. Each had only ever received treatment with either enzyme-inducing (n = 52) or non-inducing (n = 26) AEDs. Individuals were matched for age, sex, height and weight with a drug-naive control. All patients underwent bone densitometry at the lumbar spine and femoral neck and had blood sampling and urine collected for a range of bone markers. Male patients had lower BMD than controls at the lumbar spine (P < 0.01) and neck of the femur (P < 0.005). Female patients had significantly reduced bone density at the femoral neck (P < 0.05) only. AED usage was independently associated with an overall reduction in bone density at femoral sites and contributed to just over 5% of the variance at the femoral neck. Duration of treatment and type of AED were not independent factors for reduction in BMD. This case-controlled study supports the hypothesis that long-term AED therapy is an independent risk factor for reduced BMD in epileptic patients. Adults receiving treatment for epilepsy are at higher risk of osteoporosis and should be offered bone densitometry., (Copyright 1999 BEA Trading Ltd.)

Felbamate (FBM) is a relatively novel anticonvulsant agent which has been reported to exert its antiepileptic effects by blockade of the glycine recognition site on the N-methyl-D-aspartate subtype of glutamate receptor and potentiation at the gamma-aminobutyric acid (GABA) type A receptor. An increasing number of antiepileptic drugs have, however, additional, neurochemical actions on the GABA and glutamate systems which may contribute to their anticonvulsant activity. As a result, we have investigated the effects of FBM on several GABA- and glutamate-related neurochemical parameters in mouse brain. Adult male ICR mice were randomised into two groups and administered FBM (0-100 mg kg(-1)) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed for analysis of GABA, glutamate and glutamine concentrations and activities of GABA-transaminase and glutamic acid decarboxylase. Single and repeated doses of FBM were without effect on all of the parameters investigated. These results appear to exclude the possibility that FBM, in addition to its known effects on GABA and glutamate receptors, exerts its antiepileptic effects via an action on the GABA- and glutamate-related neurochemical parameters chosen for investigation., (Copyright 1999 Academic Press.)

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.

Old age is recognized to be the commonest time in life to develop epilepsy. There is a perception that older patients are more sensitive to the deleterious cognitive effects of antiepileptic drugs (AEDs). Elderly patients (median age 70 years, range 60-88 years) taking anticonvulsant monotherapy (10 carbamazepine [CBZ], 8 sodium valproate [VPA], 5 phenytoin [PHT]) took an extra dose of their usual medication (200mg CBZ, 500mg VPA, 100mg PHT) and matched placebo each for a month in random order. The concentrations of AEDs were higher after 7 and 28 days of active treatment compared with placebo (7 days: CBZ 9.5 vs. 7.8 mg L(-1), p < 0.05; VPA 97 vs. 64 mg L(-1), p < 0.05; PHT 13 vs. 11 mg L(-1), p < 0.05; 28 days: CBZ 9.4 vs. 7.7 mg L(-1); p < 0.01, VPA 85 vs. 60 mg L(-1), p < 0.05; PHT 16 vs. 13 mg L(-1), p < 0.05). Despite these increases in concentration, there were no significant changes in attention, reaction time, finger tapping, memory, side-effect scale or sedation scoring during the active phases compared with placebo phases for the three drugs analysed together and separately. Elderly patients taking standard AEDs as monotherapy did not develop cognitive impairment when the dose was modestly increased within the target range for each drug.

Fifty patients with refractory partial seizures took part in a prospective, observational study of adjuvant gabapentin (GBP) in increasing doses. Thirty-three were started on 400 mg GBP daily with further weekly increments of 400 mg until seizures came under control for at least 6 months or to the limit of tolerability. A further 17 patients, not fully controlled on low dose GBP, followed the same regimen. All patients took the drug three times daily. Comparisons were made with seizure numbers during a 3-month baseline during which antiepileptic medication remained unchanged. Overall, 24 of the 50 patients documented a seizure reduction of 50% or more. Fifteen did so at or below 2400 mg GBP daily. Three of these patients became seizure-free. The remaining nine appeared to respond to higher daily doses of GBP (1:2800 mg; 3:3600 mg; 1:4000 mg; 1:4800 mg; 3:6000 mg), with two becoming seizure-free. Side-effects most commonly reported included tiredness, dizziness, headache and diplopia. On GBP doses exceeding 3600 mg daily, three patients developed flatulence and diarrhoea and two more had myoclonic jerks. Mean circulating GBP concentrations (mg/l) at each 1200 mg dose level were as follows: 1200 mg-4.1; 2400 mg-8.6; 3600 mg 13.2; 4800 mg 15.5; 6000 mg-17.2. In six patients, including three taking 6000 mg daily, GBP concentrations continued to rise linearly at each dosage increment. Although limited, our results do not support the suggestion that GBP absorption is saturable. High dose GBP may be effective in controlling seizures in patients with refractory partial epilepsy.

Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.

1. The effects of repeated administration of the anticonvulsant compounds, vigabatrin (VGB) and tiagabine (TGB), on gamma-aminobutyric acid (GABA) concentration and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) were investigated in mouse cortex. 2. VGB alone increased GABA levels and decreased GABA-T and GAD activities. 3. TGB alone was essentially without effect. 4. Low doses of VGB and TGB in combination increased GABA levels when neither drug had such an effect alone. 5. Despite this observation, this study failed to establish any conclusive evidence for an interaction between VGB and TGB that might help to explain their reported clinical synergism.

Levetiracetam is a novel antiepileptic agent with a wide spectrum of activity against experimental and clinical seizures. The mechanism of its anticonvulsant action remains to be determined. We have investigated the effects of levetiracetam on several gamma-aminobutyric acid (GABA)-related neurochemical parameters in mouse brain. Adult male mice were randomised into two groups and administered levetiracetam (0-300 mg/kg) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of GABA, glutamate and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single dose and repeated levetiracetam treatments were without effect on all of the parameters investigated. The anticonvulsant action of levetiracetam is unlikely to be mediated via an action on the GABAergic system.

Tiagabine (TGB) and vigabatrin (VGB) are two novel anticonvulsant compounds reported to exert their pharmacological effects via an action on the gamma-aminobutyric acid (GABA) system. We have investigated the effects of acute exposure of these drugs on the uptake of GABA into rat cortical astrocytes in primary culture. Astrocytes were prepared from the cerebral cortices of one day-old rat pups by a mechanical dissociation technique and were assayed for GABA uptake activity after 21 days in culture. Tiagabine (100-300 nM) and VGB (100 microM) reduced GABA uptake when compared to control at four hours post-exposure. GABA uptake was also reduced following eight and 24 hour exposures to 200 nM TGB. A combination of TGB (200 nM) and VGB (100 microM) treatments reduced GABA uptake when compared to both control and VGB treated cultures. These results support the efficacy of TGB as a GABA uptake inhibitor and suggest that VGB may also exert an effect by this mechanism.

A rapid and simple method for determination of the novel antiepileptic compound gabapentin [1-(aminomethyl)cyclohexaneacetic acid] in plasma is described. Blank human plasma was spiked with gabapentin (1.0-10.0 micrograms/ml) and internal standard [1-(aminomethyl)-cycloheptaneacetic acid; 5.0 micrograms/ml]. Individual samples were treated with 2 M perchloric acid, centrifuged and then derivatised with o-phthalaldehyde-3-mercaptopropionic acid. Separation was achieved on a Beckman Ultrasphere 5 microns reversed-phase column with mobile phase consisting of 0.33 M acetate buffer (pH 3.7; containing 100 mg/l EDTA)-methanol-acetonitrile (40:30:30, v/v). Eluents were monitored by fluorescence spectroscopy with excitation and emission wavelengths of 330 and 440 nm, respectively. The calibration curve for gabapentin in plasma was linear (r = 0.9997) over the concentration range 1.0-10.0 micrograms/ml. Recovery was seen to be > or = 90%. The inter- and intra-assay variations for three different gabapentin concentrations were < or = 10% throughout. The lower limit of quantitation was found to be 0.5 microgram/ml. Chromatography was unaffected by a range of commonly employed antiepileptic drugs or selected amino acids.

The anticonvulsant effect of the dihydropyridine calcium channel blocker, nimodipine (NMD) was evaluated against electroshock-induced seizures in mice. At 1 h postdosing, NMD elicited a dose-dependent reduction in the occurrence of tonic hindlimb extension (THE) after maximal electroshock (MES). The calculated ED50 for NMD was 87 mg/kg. A single dose of NMD (75 mg/kg) produced a significant (p < 0.05) reduction in occurrence of THE for < or = 12 h postdosing. NMD was detectable for < or = 6 h, and plasma and brain drug concentrations correlated well (r = 0.677, p < 0.01) for that period. At 1 h postdose, a single dose of NMD (75 mg/kg) produced a 40% increase (p < 0.001) in the threshold for tonic seizures as determined by minimal electroshock (Min-ES). NMD is an effective anticonvulsant against experimental seizures induced by electroshock. The pharmacodynamic effect of NMD appears to extend beyond the time anticipated from the pharmacokinetic profile.

1. Nicotinylalanine is an analogue of kynurenine which has been reported to inhibit the enzymes kynurenine hydroxylase and kynureninase. 2. In the present study rats were given a tryptophan load together with nicotinylalanine two hours before killing, and the brain, liver and kidneys analysed by HPLC for their kynurenic acid content. 3. Tryptophan alone produced a significant elevation of kynurenate but with the additional administration of nicotinylalanine, levels rose dramatically, including a 19-fold increase in brain. 4. In mice the same dose of nicotinylalanine reduced the incidence of seizures induced by leptazol or electroshock treatment. 5. Since kynurenic acid is an antagonist at excitatory amino acid receptors the results may herald a new approach to producing a pharmacological blockade of amino acid receptors in the brain.