Discrepancies between physicians' prescriptions and patients' use of antiepileptic drugs.

OBJECTIVES: The purpose of this study was to investigate whether prescribed antiepileptic drugs (AEDs) were consistent with what patients actually used, and to explore challenges in treatment and reasons for possible discrepancies according to patients' view of their medication. MATERIAL AND METHODS: Anonymized data were collected from a questionnaire distributed to in- and outpatients and their physicians at the National Center for Epilepsy, Norway. They were asked to report AEDs and dosages currently used. Additionally, 20 patients were interviewed regarding AED treatment. This information was analyzed qualitatively. RESULTS: Answers from 174 patients and their physicians were analyzed. The patients' mean age was 43 years (21-83 years), 85 (49%) were women, and 56% used AED polytherapy (2-5 AEDs). For 56 patients (32%), there was a discrepancy regarding either dosage (n = 70) or prescribed drug (n = 32) (12%). There were discrepancies for all top 10 used drugs, with a similar distribution of patients stating lower or higher doses. Based upon interviews of 20 patients, concerns and challenges in AED treatment were addressed. Polytherapy and adverse effects which reduced the patients' quality of life were the most important obstacles for adherence to the treatment. CONCLUSIONS: This study revealed that 32% of the patients had one or more discrepancies between what the physician had prescribed and what the patients actually used, in either the type or the dosages of AEDs. Polytherapy, adverse effects, and poor adherence were common challenges. Improved communication and information about AEDs may improve adherence and thus treatment outcome.

Withdrawal of antiepileptic drugs during presurgical video-EEG monitoring: an observational study for evaluation of current practice at a referral center for epilepsy.

OBJECTIVES: Withdrawal of antiepileptic drugs (AEDs) before and during video-EEG-monitoring is commonly implemented to reduce time needed to register a sufficient number of seizures during presurgical evaluation. There are, however, few guidelines regarding withdrawal rate and observation time. MATERIAL AND METHODS: We performed an observational study including sixty patients admitted to the national Norwegian epilepsy centre and registered tapering of AEDs and their effect on seizure rate and possible complications. RESULTS: The mean daily seizure rate before admission to the EMU was 0.4 (range 0.02-4) increasing to 1.1 (range 0-8) at the EMU. 29 patients (48%) followed a slow tapering rate whereas 31 (52%) had an intermediate tapering rate. There was no significant difference between the patients with a daily seizure rate during LTM of more or <0.7 seizures per day, an increase of seizure frequency from habitual to during LTM of more or <3.3 or 6.9 with regard to rate of tapering (slow vs intermediate) etiology or AED monotherapy vs polytherapy. Twenty-six patients (43%) had a sufficient number of seizures registered within 3 days to conclude regarding the presurgical evaluation. Two patients received escape treatment while 25 patients did have 24 h-seizure-clusters. There was no serious event. CONCLUSIONS: Less than 50% of the patients got a sufficient number of seizures for a conclusive result within 3 days. An increase in the registration period could increase the number of successful registrations.

Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI).

The Sixth Eilat Conference on New Antiepileptic Drugs (AEDs) took place in Taormina, Sicily, Italy from 7th to 11th April, 2002. Basic scientists, clinical pharmacologists and neurologists from 27 countries attended the conference, whose main themes included dose-response relationships with conventional and recent AEDs, teratogenic effects of conventional and recent AEDs, update on clinical implications of AED metabolism, prevention of epileptogesis, and seizure aggravation by AEDs. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs, which have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including carabersat (SB-204269), CGX-1007 (Conantokin-G), pregabalin, retigabine (D-23129), safinamide, SPD421 (DP-VPA), SPM 927, talampanel and valrocemide (TV 1901). Updates on fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, new formulations of valproic acid, and the antiepileptic vagal stimulator device are also presented.

Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V).

The Fifth Eilat Conference on New Antiepileptic Drugs (AEDs) took place at the Dan Hotel, Eilat, Israel, 25-29 June 2000. Basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included recognition of unexpected adverse effects, new indications of AEDs, and patient-tailored AED therapy. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs that have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including AWD 131-138, DP-valproate, harkoseride, LY300164, NPS 1776, NW 1015, pregabalin, remacemide, retigabine, rufinamide and valrocemide. The potential value of an innovative strategy, porcine embryonic GABAergic cell transplants, is also discussed. Finally, updates on felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, and the antiepileptic vagal stimulator device are presented.

Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin in Refractory Epilepsy Add-on Treatment.

PURPOSE: Our objective was to compare the efficacy and safety of gabapentin and vigabatrin as first-line add-on treatment in patients with partial epilepsy. METHODS: This was a multicenter, double-blind, randomized dose titration study. After baseline assessment and randomization, the dose could be increased if seizures persisted and reduced if side effects occurred. Health-related quality of life was assessed at baseline and at the end of the study. By a protocol amendment post hoc, all randomized patients were offered a standardized perimetry examination at the end of the study. Improvement rate was the proportion of patients with a reduction of seizure frequency of at least 50% during an 8-week period without any adverse events causing withdrawal. RESULTS: One hundred two patients were randomized and analyzed on an intent-to-treat basis. The improvement rate was 48% in the gabapentin group and 56% in the vigabatrin group. The improvement rate, when per protocol criteria were fulfilled, was 57% in the gabapentin group and 59% in the vigabatrin group. The proportion of seizure-free patients was 31% in the gabapentin group and 39% in the vigabatrin group. There was no difference in quality-of-life scores between the groups. Perimetry after termination of the study on 64 patients showed abnormal results in 3 of 32 patients in the vigabatrin group. CONCLUSION: Approximately one third of the patients in both groups became seizure-free. Although no major differences were seen in terms of the improvement rate between the groups, equivalence between the two drugs was not found.

[Topiramate--a new antiepileptic agents]. / Topiramat--et nytt antiepileptikum.

BACKGROUND: Topiramate is a novel antiepileptic drug that was licensed in Norway in 1997 as adjunctive treatment for patients with partial seizures. Metaanalysis of randomized controlled studies suggest that topiramate may be the most potent of the new antiepileptic drugs and have a favourable pharmacokinetic profile. At the National Center for Epilepsy we have used topiramate since 1990. We present our clinical experience with the drug. MATERIAL AND METHODS: We have, retrospectively, assessed 114 adult patients, mainly with intractable partial seizures, who received topiramate as add-on treatment. Average follow-up was 2.3 years. RESULTS: Four patients (3.5%) became seizure free. The overall seizure frequency was reduced by > 50% in 56 patients (49%). Adverse effects were observed in 82 patients (72%); in 54 patients (47%) the drug had to be withdrawn due to unacceptable side effects and/or lack of clinical effect. The most frequent side effects were weight loss, fatigue, behavioural and cognitive problems. INTERPRETATION: Our results corroborate an impression of topiramate being an effective drug used as adjuntive therapy in patients with refractory epilepsy. Side effects can be a problem, but a low starting dose, a slow dose escalation, and topiramate used alone may reduce this problem.

Therapeutic monitoring of the new antiepileptic drugs.

OBJECTIVE: To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. METHODS: A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed. RESULTS: The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM. CONCLUSION: TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration-effect relationships of the new antiepileptic drugs are urgently needed.

[Epilepsy and pregnancy]. / Epilepsi og graviditet.

Based on recent international consensus conferences and a literature search, a brief summary is given of current knowledge about epilepsy in pregnancy. We suggest new Norwegian guidelines based on international recommendations for handling pregnant women with epilepsy. There is a slightly increased risk for malformations in children born of women with epilepsy. The main reason is probably teratogenic effects of antiepileptic drugs. Nevertheless, the overall chance of giving birth to a healthy child is 92-96%, compared to about 98% in the general population. Counselling all fertile women with epilepsy is important in order to reduce the risk of malformations. Before a planned pregnancy, medication should be re-evaluated, and the lowest dose of the drug most likely to give satisfactory seizure control is preferable. The women should have regular neurological follow-up throughout the pregnancy, and they should be given extra vitamin D, K, and folate. Women using carbamazepine, valproate or the new generation of antiepileptic drugs should be offered amniocentesis and comprehensive ultrasound examination in the 14th and 17th week, respectively. The newly approved drugs should be prescribed only if they provide a considerable better seizure control and/or fewer side effects than the traditional antiepileptic drugs.

Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV).

The Fourth Eilat Conference on New Antiepileptic Drugs (AEDs) was held at the Royal Beach Hotel, Eilat, Israel, from 6th to 10th September 1998. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss a number of issues in drug development, including outcome assessment in epilepsy (long-term efficacy, quality of life, safety), cost-effectiveness, an update on drugs in development, a progress report on recently marketed AEDs, and controversies in strategies for drug development. This review focuses on drugs in development and recently marketed AEDs. Drugs in development include ADCI, AWD 131-138, DP16, ganaxolone (CCD 1042), levetiracetam (ucb L059), losigamone, pregabalin (isobutyl GABA [CI-1008]), remacemide hydrochloride, retigabine (D-23129), rufinamide (CGP 33101), soretolide (D2916), TV1901, and 534U87. New information on the safety and efficacy of recently marketed drugs (felbamate, fosphenytoin, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide) and of a new antiepileptic device, the neurocybernetic prosthesis (NCP), has become available. This paper summarizes the presentations made at the conference.

[Gabapentin--a new antiepileptic agent]. / Gabapentin--et nytt antiepileptikum.

Gabapentin is a new antiepileptic drug. Its mechanism of action is not clearly understood, but it seems to differ from that of other antiepileptic drugs. The favourable pharmacokinetic properties of gabapentin make it simple to use. Our preliminary clinical observations with gabapentin at the National Center for Epilepsy are presented. 58 adult patients (mean age 28.9 years), mainly with refractory partial seizures, had gabapentin added to their existing medication. The follow-up period was 6.9 months on average. Only one patient experienced a reduction in seizures of more than 50%, while 25 patients experienced a moderate reduction in seizures (10-50%). The clinical effect was most favourable in patients with secondary generalized tonic-clonic seizures. Gabapentin was well tolerated, and no clinically significant interactions were encountered. Recent observations show that the doses of gabapentin used in our study may have been too low.

Lidocaine pharmacokinetics and toxicity in newborn pigs.

In newborn infants suffering from perinatal asphyxia seizures, lidocaine (LD) has proved to be an effective anticonvulsant. At high concentrations, however, LD can itself cause convulsions. The convulsive concentration of LD (LD(conv)) varies among species. The aim of this study was to describe LD pharmacokinetics and to define the LD(conv) in awake newborn pigs. Eighteen Land race newborn pigs aged 12-60 h, weight 1.0-2.5 kg, were enrolled. LD, 2 mg/kg intravenous (IV) bolus, (n = 11) was given to estimate pharmacokinetic variables. Continuous LD infusion 2 mg x kg(-1) x min(-1) IV (n = 5) and repeated bolus doses of 15 mg/kg (n = 4) were given until electroencephalogram-confirmed seizures appeared. After the bolus injection, the elimination half-life for LD was 0.87-5.44 h. Increasing plasma concentration (LD(pl)) during infusion resulted in sedation after 5-10 min and in shivering, nystagmus, neck extension, tonic-clonic seizures at LD(conv) of 40.6 +/- 12.7 mg/L (mean +/- SD). The unbound LD(pl) at seizures was 4.4 +/- 2.4 mg/L. Younger animals convulsed at higher LD(conv) (r2 = 0.85). LD pharmacokinetics in newborn pigs were found to be dose-dependent at high plasma concentrations. At lower plasma concentrations, LD pharmacokinetics appeared to be linear. The central nervous system is the primary target for the toxic effect of LD in awake newborn pigs. LD neurotoxicity is age-dependent, and younger pigs convulse at a higher LD(conv).

[Serum digitoxin in concomitant use of antiepileptics in routine therapy]. / Serum-digitoksin ved samtidig bruk av antiepileptika i rutinebehandling.

Concomitant use of digitoxin and enzyme-inducing antiepileptics may lower serum levels, and accordingly the effect of digitoxin, unless the higher metabolic clearance is compensated for by higher dosage. Use of digitoxin is almost always guided by serum concentration measurements. Information on a possible enzyme-inducing effect of phenobarbital, phenytoin and carbamazepine is easily accessible. Compilation of serum level measurements for digitoxin showed that serum levels shifted towards lower values during concomitant use of phenytoin or carbamazepine than when digitoxin was used alone. As a consequence, the fraction of patients with serum levels below the therapeutic range was doubled. Concomitant use of phenobarbital did not cause a shift in the levels of digitoxin. In fact, in this group, a larger fraction of the serum level measurements were within the therapeutic range. Thus, the dosage of digitoxin appears to be fully compensated during concomitant use of phenobarbital, but obviously deserves attention during concomitant use of phenytoin or carbamazepine.

Pharmacokinetics and interaction profile of topiramate: review and comparison with other newer antiepileptic drugs.

Standard antiepileptic drugs (AEDs) have a number of pharmacokinetic shortcomings, and AEDs with more favorable profiles would be preferred. The pharmacokinetics and interaction profile of the recently developed AED topiramate (TPM), is reviewed and compared with those of other newer AEDs including lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB), and oxcarbazepine (OCBZ). Although none of these agents meets all of the criteria of the "ideal" AED from the pharmacokinetic standpoint, a number of these drugs, including TPM, have desirable properties that distinguish them from the older AEDs and should contribute to their clinical utility.

Progress report on new antiepileptic drugs: a summary of the Third Eilat Conference.

The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues in drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.

Progress report on new antiepileptic drugs. A summary of the Second Eilat Conference.

The Second Eilat Conference on New Antiepileptic Drugs was held at the King Solomon's Palace Hotel from October 31 to November 3, 1994. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss new trial designs, drug approval, early use of new antiepileptic drugs, and new drugs in development. Over the last six years, several novel antiepileptic drugs have been introduced worldwide, and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, and vigabatrin. Drugs in development include those at an advanced stage, such as topiramate and tiagabine, as well as those just entering clinical trials, such as remacemide and levetiracetam. The following is a summary of the presentations for drugs in development and newly marketed drugs. The meeting concluded with a presentation, 'Still Searching for the Magic Bullet'.

[Vigabatrin--a new antiepileptic agent]. / Vigabatrin--et nytt antiepileptikum.

The new antiepileptic drug vigabatrin acts by preventing degradation of the inhibitory neurotransmitter GABA (gammaaminobutyric acid). This appears to decrease propagation of abnormal hypersynchronous discharges, thus reducing seizure activity. In an open study in 46 patients with intractable epilepsy, supplementary therapy with vigabatrin reduced seizure by at least 50% in 15 patients. Three patients became seizure-free. The best effect of vigabatrin is seen in patients with partial epilepsy. Tiredness and irritability were the most frequently reported side effects, but these were usually mild and transient.