Peripheral retinal dysfunction in patients taking vigabatrin.

OBJECTIVE: To assess the wide-field multifocal electroretinogram (WF-mfERG) for assessment of retinal function in vigabatrin-treated patients. METHODS: Thirty-two adults who had taken vigabatrin for at least 3 years for localization-related epilepsy underwent WF-mfERG, ERG, logMar visual acuity and color vision evaluation, Humphrey visual field analysis (static perimetry), and funduscopy. The group was matched with a cohort of patients who had never received vigabatrin. Results were compared with a normative data set (120 drug-free controls) with respect to potential bilateral abnormalities in response timing. RESULTS: There were no significant differences between groups in visual acuity or color vision testing. Of the vigabatrin patients, 19 (59%) had bilateral visual field defects compared to none of the controls. Using WF-mfERG, all patients on vigabatrin with visual field defects showed abnormalities (100% sensitivity) and only 2 of the 13 patients without a field defect showed retinal abnormalities (86% specificity). CONCLUSIONS: WF-mfERG may be useful for detecting retinal pathology in patients taking vigabatrin. The majority of previous reports based on subjective testing may have underestimated the prevalence of peripheral retinal toxicity related to the drug.

Current limitations of antiepileptic drug therapy: a conference review.

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.

The mechanisms of action of commonly used antiepileptic drugs.

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.

Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina.

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.

Update on the mechanisms of action of antiepileptic drugs.

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.

Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study.

There have been anecdotal reports of raised glutamic acid decarboxylase (GAD) autoantibodies in patients with refractory epilepsy. We measured serum GAD autoantibodies in 105 patients with idiopathic or symptomatic epilepsy. There was no significant difference in the absolute titre of GAD autoantibody between patients with controlled and uncontrolled epilepsy. However, four female patients with uncontrolled epilepsy had levels that were over three times above the highest detected in the seizure-free group, three of whom also tested positive for pancreatic islet cell antibodies. Larger scale studies, perhaps comparing different epilepsy syndromes, are required to determine the exact clinical role of GAD autoantibodies in epilepsy.

Simultaneous determination of remacemide hydrochloride and desglycinylremacemide (AR-R12495XX) in brain tissue by high-performance liquid chromatography.

Remacemide hydrochloride, a novel anticonvulsant agent, and its major active metabolite, desglycinylremacemide, were measured simultaneously in brain tissue by high-performance liquid chromatography with UV detection. Intra- and inter-assay variations for remacemide (1, 5, 10 microg/ml) were 5.1, 10.5 and 3.1% and 3.1, 4.0 and 1.3%, respectively. Intra- and inter-assay variations for desglycinylremacemide (1, 5, 10 microg/ml) were 4.2, 3.8 and 8.4% and 7.9, 8.8 and 3.1%, respectively. Limits of detection and quantification for both analytes were 4 and 31 ng/ml, respectively, with recovery consistently > or =85%. This reliable assay has applications in the pre-clinical neuropharmacokinetic and neuropharmacodynamic investigation of remacemide hydrochloride.

A neurochemical study of the novel antiepileptic drug retigabine in mouse brain.

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.

Topiramate in refractory epilepsy: a prospective observational study.

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.

Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt.

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.

Vigabatrin and tiagabine are pharmacologically different drugs. A pre-clinical study.

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.

Bone density and antiepileptic drugs: a case-controlled study.

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.

Neurochemical studies with the anticonvulsant felbamate in mouse brain.

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.

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

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.

Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.

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.

Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled study.

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.

High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients.

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.

Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain.

1. Remacemide hydrochloride, a recently developed antiepileptic drug, is believed to exert its effects, at least in part, via its desglycinyl metabolite, ARL 12495AA. 2. We have investigated the effects of ARL 12495AA on several neurochemical parameters in mouse brain. Adult male ICR mice were randomized into two groups and administered ARL 12495AA (0-75 mg kg-1) intraperitoneally, either as a single dose or once daily for 5 days. 3. Six hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of gamma-aminobutyric acid (GABA), glutamine and glutamate and for the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). 4. Single dose ARL 12495AA was without effect on any of the parameters investigated. 5. Repeated ARL 12495AA treatment did not alter brain concentrations of GABA and glutamine, but at a high dose there was a trend toward reduced brain glutamate concentrations (P = 0.10). 6. Repeated administration of ARL 12495AA at a high dose significantly increased GABA-T activity (P < 0.05) and decreased that of GAD (P < 0.05). 7. These findings may have relevance to the clinical use of remacemide hydrochloride in human epilepsy.

Neurochemical actions of gabapentin in mouse brain.

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.