Choice Of Antiepileptic Drugs Research Articles

Neonatal Seizures: Dilemmas in Workup and Management

There is a pressing need for consistent, evidence-based guidelines in the management of neonatal seizures by pediatric neurologists and neonatologists. Israeli pediatric neurologists and neonatologists completed a 20-item, self-administered questionnaire on choices of antiepileptic drugs, treatment of intractable neonatal seizures (unremitting seizures after 3 medications), treatment duration, and recommended workup. The responding 36/55 (65%) neurologists and 66/112 (59%) neonatologists made similar antiepileptic drug choices (phenobarbital as first line, phenytoin as second line, and benzodiazepines as third line). Antiepileptic treatment duration was similar for both groups, but varied considerably within them (range, 1-52 weeks). Neurologists tended to recommend longer treatment for seizures secondary to asphyxia or hemorrhage. Neurologists and neonatologists recommended different antiepileptic drugs for intractable neonatal seizures: valproic acid and topiramate by neurologists, vs lidocaine and benzodiazepines by neonatologists (P = 0.0023). Fewer neurologists recommended continuous electroencephalography monitoring after asphyxia than neonatologists (40% vs 70.5%, P = 0.013). These responses reflect both similarities and inconsistencies of the two groups in diagnosing and treating neonatal seizures. Our findings call for controlled clinical trials to establish protocols for (1) diagnosing neonatal seizures, (2) studying the efficacy and safety of new-generation antiepileptic drugs, and (3) determining optimal duration of drug administration.

Impact of reimbursement restrictions on the choice of antiepileptic drugs: Belgian Study on Epilepsy Treatment (BESET)

In Belgium, new and costly antiepileptic drugs (AEDs) are only reimbursed as second-line treatment, after documented treatment with conventional and cheaper AEDs has failed. The objective of this study was to describe the treatment of epilepsy in Belgium and to analyze the impact of the reimbursement restrictions on the choice of AEDs. Between May and June 2003, a sample of 100 neurologists, representative of the entire neurological community in teaching, academic, and regional hospitals in Belgium, were personally interviewed on the basis of a structured questionnaire (modified Rand method). The questionnaire contained questions on treatment choices and strategies in adult epilepsy. Unanimously, initial monotherapy was the preferred treatment strategy in all types of epilepsy. In the opinion of most neurologists, valproate was the first choice for idiopathic generalized and focal epilepsy with/without secondary generalization. Carbamazepine as their first choice for the treatment of focal epilepsy. New AEDs were most often prescribed as second-line therapy. Lamotrigine was the most frequently prescribed new AED and used for both generalized and focal epilepsy. It was followed by levetiracetam, topiramate and oxcarbazepine for focal epilepsy. In the absence of reimbursement restrictions, two new AEDs would be significantly more often prescribed as a first-line therapy: lamotrigine for idiopathic generalized epilepsy and oxcarbazepine for focal epilepsy. The neurologists reached a high level of consensus on many of the key treatment questions. Monotherapy with valproate and carbamazepine was the standard treatment strategy in Belgium. Lamotrigine and less so levetiracetam, topiramate and oxcarbazepine were commonly prescribed as second-line AEDs. In the absence of reimbursement restrictions, lamotrigine and oxcarbazepine would be more frequently prescribed.

Antiepileptic drugs in pediatric epilepsy

The epilepsies are socially handicapping disorders and even a single seizure occurring in certain circumstances may have disastrous effect. The impact of epilepsy on every aspect of both the lives of the child and family is significant. Issues such as mental retardation, subtle neuropsychologic disturbances, cognitive problems, behavioral problems and learning difficulties are major factors affecting the children with epilepsy. Drug treatment is the major form of therapy for a vast majority of children with epilepsy. The choice of antiepileptic drugs (AEDs) in a child depends on the type of seizures, syndrome diagnosis, age of the patient and its consequent adverse effects. The metabolism of AED also differs according to the pediatric age group, requiring different dose regimens. Here, a brief review of AED used in the pediatric age group is presented.

Multiple treatment comparisons in epilepsy monotherapy trials

BackgroundThe choice of antiepileptic drug for an individual should be based upon the highest quality evidence regarding potential benefits and harms of the available treatments. Systematic reviews and meta-analysis of randomised controlled trials should be a major source of evidence supporting this decision making process. We summarise all available individual patient data evidence from randomised controlled trials that compared at least two out of eight antiepileptic drugs given as monotherapy.MethodsMultiple treatment comparisons from epilepsy monotherapy trials were synthesized in a single stratified Cox regression model adjusted for treatment by epilepsy type interactions and making use of direct and indirect evidence. Primary outcomes were time to treatment failure and time to 12 month remission from seizures. A secondary outcome was time to first seizure.ResultsIndividual patient data for 6418 patients from 20 randomised trials comparing eight antiepileptic drugs were synthesized. For partial onset seizures (4628 (72%) patients), lamotrigine, carbamazepine and oxcarbazepine provide the best combination of seizure control and treatment failure. Lamotrigine is clinically superior to all other drugs for treatment failure but estimates suggest a disadvantage compared to carbamazepine for time to 12 month remission [Hazard Ratio (95% Confidence Interval) = 0.87(0.73 to 1.04)] and time to first seizure [1.29(1.13 to 1.48)]. Phenobarbitone may delay time to first seizure [0.77(0.61 to 0.96)] but at the expense of increased treatment failure [1.60(1.22 to 2.10)]. For generalized onset tonic clonic seizures (1790 (28%) patients) estimates suggest valproate or phenytoin may provide the best combination of seizure control and treatment failure but some uncertainty remains about the relative effectiveness of other drugs.ConclusionFor patients with partial onset seizures, results favour carbamazepine, oxcarbazepine and lamotrigine. For generalized onset tonic clonic seizures, results favour valproate and phenytoin.

Epilepsy in a rural elderly population

The first goal of this study was to describe the characteristics of elderly patients with epilepsy and the antiepileptic drugs used to treat them. Next, the factors (such as epilepsy type, seizure frequency, medical comorbidities, etc.) influencing antiepileptic drug choice and living situation were explored. Retrospective chart review of patients older than 70 with epilepsy seen in a rural health care system. This yielded 449 patients with epilepsy, 54 patients with isolated seizures and 38 patients with syncope as the primary diagnosis. The most commonly used antiepileptic drug was phenytoin. New generation AED's which had fewer side effects were used much less frequently than old generation AED's but the probability of using new generation AED's was increased in patients with renal failure and congestive heart failure as well as in patients that had seen a neurologist. Patients with acute symptomatic seizures, dementia, chronic obstructive pulmonary disease, frequent seizures and advanced age were less likely to be independent. Patients that had seen a neurologist as an outpatient were more likely to live independently. The elderly are a vulnerable population because of difficulty communicating their symptoms and their needs. This leads to the suboptimal use of AED's as well as poor outcomes. Careful attention to seizure control and medication side effects is critical in promoting good outcomes in this patient group. This retrospective study suggests that access of elderly patients with epilepsy to specialty care improves outcomes in terms of living status. This important information needs to be confirmed by prospective studies.

Use of the newer antiepileptic drugs in pediatric epilepsies

Children with epilepsy, particularly infants, differ from adults not only in the clinical manifestations of their seizures but also in the presence of unique electroencephalographic patterns, etiologies, and response to antiepileptic drugs (AEDs). There is a growing list of newer AEDs and nonpharmacologic therapies available to manage childhood epilepsy. These newer AEDs may not be overall more efficacious than the older drugs, but they do appear to be safer, better tolerated, and to have fewer drug-drug interactions. Selection of the AED for initial therapy must be based upon clinical judgment and patient-specific circumstances, such as the specific epilepsy syndrome being treated, anticipated duration of treatment, presence of comorbidities, ability to use certain formulations, and overall cost effectiveness. In some cases, seizures may be aggravated by the use of certain AEDs. Overall, oxcarbazepine is the first-line treatment for localization-related epilepsy with partial-onset seizures. For generalized epilepsies, the AED choice is highly dependent upon which specific syndrome is being treated. For generalized epilepsies with primarily absence seizures, lamotrigine is the AED of first choice. For mixed generalized epilepsies such as Lennox-Gastaut syndrome or juvenile myoclonic epilepsy, zonisamide or topiramate are the first-line agents. For infants with West syndrome, treatment is based upon the underlying etiology: vigabatrin for tuberous sclerosis; adrenocorticotropic hormone for children with no specific etiology uncovered (cryptogenic); and zonisamide for those with a severe symptomatic etiology other than tuberous sclerosis. Single drug therapy (monotherapy) is the goal of epilepsy treatment because this is associated with better compliance, fewer adverse effects, and lower cost. If the seizures prove intractable or adverse effects are encountered with the first AED, then a second monotherapy trial is undertaken. Once three appropriate medications at therapeutic doses have failed, other modalities should be considered, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet.

Optimizing therapy of seizures in patients with HIV and cysticercosis

Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.

EEG Features in Idiopathic Generalized Epilepsy: Clues to Diagnosis

To the Editor: We read with interest the article by Betting et al., 2006 entitled “EEG Features in Idiopathic Generalized Epilepsy: Clues to Diagnosis (1).” The authors investigated the contribution of EEG recordings for diagnosis and management of 180 patients with a clinical diagnosis of idiopathic generalized epilepsy (IGE). They found that the first EEGs yielded 45% with normal activity, 55% with abnormal activity, and only 33% indicated typical abnormalities. Patients with absence epilepsy were most likely to exhibit specific EEG abnormalities. At the time of EEG evaluation 92% of the patients were taking an AED and 80% of the patients had remained seizure free for ≥ 1 year. From this information the authors concluded that clinical history contributes more to the diagnosis of IGE and that treatment may be inappropriately delayed while “waiting” for a typical abnormal pattern on EEG. Significant studies on the predictive value of EEG after the first unprovoked seizure have revealed contradictory results. Some studies have shown EEG abnormalities in up to 70% of patients after an initial unprovoked seizure (2). Others have shown that obtaining an EEG provides little additional information in further treatment of the patients (3). In fact, our group has previously shown that extended EEG monitoring is important in establishing the diagnosis of the type of epilepsy and making an appropriate choice of antiepileptic drug (AED) therapy in the future care of patients (4, 5). Indeed, the accurate diagnosis of idiopathic generalized epilepsy was confirmed after prolonged EEG monitoring in only 29% of patients (5). Further controversy exists on whether risk for seizure recurrence is increased by the presence of an abnormal EEG on first examination. Several studies have demonstrated that the risk of recurrence doubles with an abnormal EEG (6, 7). We recommend caution when interpreting the results of this study. Our main reservation is that EEG interpretations were performed independent of whether the patient was receiving AED treatment or not. Studies have demonstrated normalization of EEGs while on AED therapy (8). Moreover, the EEG data was not assessed in patients with new onset seizures only. Initial EEGs were performed in some patients up to 44 years after seizure onset. We understand that in situations where resources are limited, there may be delays before performing an EEG. In this situation, we agree with the authors that AED treatment should not be withheld from a patient with seizures while “waiting” for an EEG. However, EEG is and will continue to be an important investigation in the diagnosis, treatment, and prognosis of patients with epilepsy.

P30.13 Mental processing in epilepsy in children and adolescents

Long latency auditory evoked potentials, especially P300, are an objective and non-invasive procedure and a recommended standard for clinical evaluation of mental processing. Aim of the study: In order to evaluate the results of epilepsy treatment in children and adolescents the influence of two antiepileptic drugs (AED) carbamazepine (CBZ) and valproates (VPA) on cognitive functions was analyzed. Materials and methods: The examination was performed in 30 newly diagnosed patients with epilepsy 8–18 years old before AED therapy and in 62 patients to whom both formulations of CBZ or VPA was administered in monotherapy. Neuropediatric status as well as the neuroimaging in the groups were unremarkable. All showed normal mentality measured by psychological tests. Control group consisted of 66 healthy children and adolescents of the same age. According to the IFCN standards, we applied the oddball paradigm to elicit P300. Results: Significant prolongation of P300 and N2 latency was observed and the increase of N1–P2, P2–N2 and N2–P3 amplitude values in all epileptic patients in comparison to healthy controls was detected. There were also significant changes of N1 and P2 latency recorded in children receiving CBZ. P300 latency was longer in patients with newly diagnosed epilepsy than in control group. It was also shown that patients with partial seizures demonstrated longer P300 and N2 latency than recorded in case history as well as N2–P3 amplitude was higher than in patients with generalized seizures. There was not any statistically significant relation between parameters of P300 and the age of the child at the moment of epilepsy being diagnosed, the duration of the disease and the level of AED in blood serum. Conclusions: There were significant differences indicated in parameters of P300 in epileptic children and adolescents in comparison to control group. The type of epileptic seizures and the choice of AED influence their values significantly.

Seizure aggravation by antiepileptic drugs

Seizure aggravation by antiepileptic drugs (AEDs) is an overestimated phenomenon. While it undoubtedly occurs, the quality of evidence in most published reports is poor. Although seizure aggravation can be examined in clinical trials in the same way as seizure improvement, this is rarely done. Before concluding that an increase in seizures after the introduction of a new drug represents pharmacodynamic aggravation, alternative explanations should be explored. These include spontaneous fluctuation of seizure frequency, the presence of known seizure aggravators (such as sleep deprivation, alcohol, and psychotropic medications), progression of epilepsy, the development of drug resistance, and replacement of a partially effective drug with a less effective drug. The risk of incorrectly blaming a drug for a deterioration in seizures can be minimized by establishing baseline seizure frequency over a period long enough to encompass the extremes of seizure fluctuation and by educating the patient that a temporal relationship may not be a causal relationship. When feasible, the patient should continue the drug long enough to establish if the deterioration is transient. If the drug is stopped, rechallenge should be considered. The risk of seizure aggravation can be minimized by accurate diagnosis of the epilepsy syndrome and appropriate choice of AED.

Antiepileptic drugs: properties and recommended use

The choice of antiepileptic drug is principally dictated by seizure type, co-morbidity and risk of drug interactions. In our Drug review the authors describe the diagnosis and cur rent management of epilepsy, followed by an analysis of prescription data, sources of fur ther information and the Datafile. Copyright © 2006 Wiley Interface Ltd

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses >1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.

Aggravation of epilepsy by anti‐epileptic drugs

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.

Epilepsia en ancianos

Epilepsy is a frequent pathology in the elderly, but its aetiology, clinical presentation and prognosis are different to those seen in younger patients.Beyond a certain age physiological modifications take place in the metabolism that alter the pharmacokinetics of the antiepileptic drugs (AED) and increase the risk of pharmacological interactions, which is already higher in these patients owing to the frequency of polypharmacy. Moreover, elderly patients are especially sensitive to certain side effects of AED, such as cognitive disorders, osteoporosis or weight increase. Since the efficacy of the more important AED is a priori quite similar and the epilepsies we have to deal with at this age usually have a good prognosis, the choice of AED will depend more on their pharmacokinetics and their potential to trigger certain side effects than on their effectiveness.The ones with the most favourable pharmacokinetic profile are levetiracetam and pregabalin, followed oxcarbazepine and lamotrigine. Additionally, these drugs generally have few cognitive effects, do not give rise to osteoporosis and, with the exception of pregabalin, do not alter the patient's weight, all of which makes them first choice drugs for the treatment of epilepsy in the elderly.

Pharmacogénétique et traitements antiépileptiques

This chapter presents the pharmacogenetics of antiepileptic drugs. Pharmacogenetics considers the influence of the individual genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Today, two polymorphisms of the cytochrome P 450 2C9 are known to slow phenytoin metabolism and thus to bear a considerable risk of drug neurotoxic side effects among carriers of this polymorphism. Apart from this example of immediate clinical importance, this chapter focuses on future directions of pharmacogenetic research such as the consequences of channelopathies on the choice of antiepileptic drugs, on aspects of drug resistance associated with multidrug transporters and “idiosyncratic” side effects.

Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs

Women with epilepsy are believed to be at risk for sexual dysfunction. Disorders of sexual desire and sexual arousal, including dyspareunia, vaginismus, and lack of lubrication, affect an estimated 30 to 60% of women with epilepsy. In this study, 57 reproductive-aged women with either localization related (LRE) or primary generalized epilepsy (PGE) on antiepileptic drug (AED) monotherapy and 17 nonepileptic controls completed questionnaires examining sexual experience, arousability, anxiety, and symptoms, as well as an inventory of depression. An endocrine assessment was performed during the early follicular phase of the menstrual cycle. Sexual dysfunction was more common in women with LRE, in women receiving phenytoin, in women with low levels of estradiol and dehydroepiandrosterone sulfate, and in women with self-reported symptoms of mild depression. The mechanisms of sexual dysfunction in women with epilepsy are multifactorial, but AED choice appears to be one cause that is modifiable.

Choice of antiepileptic drug, which one to try first and what to do if it fails ...

Choice of antiepileptic drug, which one to try first and what to do if it fails ...

The choice of antiepileptic drugs in newly diagnosed epilepsy: a national French survey

The choice of an antiepileptic drug (AED) in patients with epilepsy is mainly based on efficacy and safety of each drug. However, these criteria of drug selection should be further evaluated according to the epileptic syndromes, and adjusted to the sex and age of the patient. Unfortunately, very few studies have been conducted based on these latter criteria. We conducted a survey on the management of epilepsy treatment in adults. This survey was undertaken in France, and led to the establishment of a French consensus on antiepileptic drug treatment in adult patients with newly diagnosed epilepsy. Patients were grouped into 18 categories according to the epileptic syndrome (absence epilepsy, juvenile myoclonic epilepsy, undetermined idiopathic generalized epilepsy, symptomatic or cryptogenic partial epilepsy and unclassified epilepsy), and to the patient's gender and age. Our survey suggests that there is a consensus among French epileptologists for the choice of AEDs, mainly based on the epilepsy syndrome. Gender also plays a crucial role. Sodium valproate and lamotrigine are the two drugs of choice for generalized epilepsies, as well as for undetermined epilepsies. Lamotrigine is often prefered for women of childbearing age. First line AEDs in partial epilepsy are carbamazepine (particularly for men), lamotrigine (particularly for women), and gabapentin (in the elderly). In cases of failure and/or intolerance to one of these AED, the principal alternatives are oxcarbazepine, sodium valproate and topiramate.

Prescribing antiepileptic drugs: should patients be switched on the basis of cost?

To assess the costs of switching from one antiepileptic drug (AED) to another, all associated direct and indirect costs, not only drug acquisition costs, must be considered. The perspective of the healthcare system evaluated in cost-effectiveness analysis is of crucial importance. Multiple clinical factors can influence clinical decisions regarding switching AEDs. The economic cost of poorly controlled epilepsy is enormous and the most cost-effective intervention is an AED that provides total seizure control. Cost-minimisation studies have evaluated costs associated with various medications. If only efficacy and adverse events were considered, then the 'older' AEDs were generally more cost effective than the 'newer' AEDs. Most studies only examine very specific clinical situations and are not suitable for establishing general clinical recommendations. The pharmacoeconomics of AED choice is highly country specific. While switching to generic formulations is, in general, cost effective, some changes may be detrimental and more costly than remaining on the trade name preparation. For example, as a result of differences in bioavailability and possible loss of seizure control, changing patients to generic phenytoin and carbamazepine can be problematic. Fosphenytoin may only be cost effective in certain clinical situations compared with intravenous phenytoin. Seizure control should not be sacrificed on the basis of costs alone, as the major endpoint in treating epilepsy with AEDs is seizure control without adverse effects. Switching AEDs in clinical practice still depends on the individual clinical situation and choosing AED therapy solely on the basis of initial acquisition costs is unlikely to be cost effective in the long-term care of patients with epilepsy.

Idiopathic generalized epilepsy and choice of antiepileptic drugs.

The authors reviewed 58 patients with EEG-confirmed idiopathic generalized epilepsy (IGE). When initially seen, 17 (29%) were on broad-spectrum (adequate) antiepileptic drugs (AED) only, 28 (48%) on ill-advised AED only, and 13 (22%) on a combination of both. Thus, a majority of patients with IGE initially receive ill-advised AED, which cause IGE to appear intractable.