Randomised controlled monotherapy trials: which comparators to use?

As approximately 50% of patients with newly diagnosed epilepsy achieve seizure remission after initial monotherapy, the selection of the first-choice drug to be used as the gold standard in randomised clinical trials is critical. Several first and second generation drugs have been used in regulatory and pragmatic monotherapy trials with similar efficacy but differing pharmacokinetic, tolerability, and safety profiles. None of the available compounds has an ideal profile and second generation drugs do not appear to present unequivocal advantages in this regard. Compared to first generation drugs, some newer generation antiepileptic drugs may be preferred as they have similar efficacy but lower potential for idiosyncratic reactions and drug interactions. However, more recent antiepileptic drugs also have limitations, which include lack of superiority and, in some cases, unbearable adverse effects. In this light, there are no standard criteria as a reference for the selection of the best comparator for new monotherapy trials. However, according to the recommendations of evidence-based guidelines, carbamazepine still represents the first-choice drug for patients with partial epilepsy. Ethosuximide may be an option for absence epilepsy. In contrast, for the treatment of patients with other generalised epilepsies, there is no clear indication of preferred drug, as valproate, which has been found to prevail over other compounds, should be withheld in women of childbearing age due to its teratogenic potential, and there is insufficient evidence to choose an alternative drug.     

Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy

The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.     

Epilepsy: from consensus to daily practice

Most clinicians would accept that epilepsy treatment should begin with monotherapy, and in the majority of cases this is the preferred drug maintenance option. The clinical choice of one antiepileptic drug (AED) over another should be based on firm evidence of efficacy and tolerability as evaluated in comparative monotherapy studies and pharmacokinetics. This paper presents the findings of evidence-based reviews of AED monotherapy in patients newly diagnosed with epilepsy. The main study was conducted in the United Kingdom and investigated the clinical evidence supporting AEDs used as first-line monotherapy. In this paper the general treatment recommendations will focus on valproate, one of the mainstay drugs used in the fight against epilepsy. Finally, with these recommendations in mind, the principles behind AED drug selection in clinical practice will be discussed. Factors for consideration that impact on AED decision-making include: seizure and syndrome diagnosis, AED tolerability profiles, patient characteristics and pharmacokinetic/pharmacodynamic AED interactions.     

Epilepsie und Leistungssport – ermutigende Ergebnisse

Modified-release antiepileptic drugs are known to reduce central nervous system- (CNS-)related adverse drug reactions. This could be demonstrated for the “old” antiepileptic drugs, such as valproic acid or carbamazepine. For the new, modified-release oxcarbazepine formulation (OXC-MR, Apydan® extent) benefit concerning better tolerability could also be shown. This case report of a patient with epilepsy under antiepileptic treatment with OXC-MR, who pursues successful competitive sports at a high level with high physical and concentration efficiency, demonstrates the very good CNS tolerability of this pharmaceutical form.     

Old and new antiepileptic drugs during pregnancy and lactation--report of a case

We describe a case of a woman with epilepsy treated with primidone/phenobarbital (so-called "old" antiepileptic drug) and levetiracetam (so-called "new" antiepileptic drug) who was discouraged from breastfeeding, resulting in clinically significant withdrawal seizures in her newborn. As a consequence, even when two or more antiepileptic drugs are needed for the treatment of women with epilepsy, breastfeeding should be recommended, mothers should be informed about the possibility of drug effects on the neonate, and infants of mothers treated with primidone/phenobarbital should be closely monitored for possible signs of sedation.     

Therapeutic strategies in the choice of antiepileptic drugs

The choice of treatment of newly diagnosed epilepsy involves many factors such as age, sex, life style, general health and concomitant medication. The seizure type, syndrome, and the pharmacology, efficacy and safety of the antiepileptic drugs (AEDs) should also be considered. Some of the new AEDs appear to provide at least equivalent efficacy with better tolerability. Some of these drugs have the potential to become drugs of first choice in newly diagnosed epilepsy. At the present time, we also must consider the criteria of reimbursement of these drugs. In this paper, we try to describe common and practical strategies to start a treatment of newly diagnosed epilepsy.     

Teratogenic effects of antiepileptic drugs

Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed.     

The use of recently approved antiepileptic drugs: use with caution, use in refractory patients or use as first-line indications?

Approximately 50% of patients with newly diagnosed epilepsy achieve immediate remission, and up to 50% enter terminal remission with first-generation antiepileptic drugs. However, 20-30% of cases are still refractory to current treatments. This population is the target of newer antiepileptic drugs and other compounds in development. The licensing of newer antiepileptic drugs represents an advance in the development of more manageable products and the control of several disturbing adverse drug reactions of the older compounds. However, despite the development of several new antiepileptic drugs, the efficacy and tolerability of drug treatment of epilepsy has not substantially improved in terms of effectiveness and risk-benefit and cost-benefit profiles. Newer antiepileptic drugs are, at best, equivalent in efficacy to their predecessors, but some of them are more manageable and better tolerated. However, the use of a first-generation compound at low doses in newly diagnosed patients is still preferable because the disease can be as well-controlled and the incidence of intolerable side effects is minimized. Newer generation compounds should be used as alternative treatments in patients who are nonresponding to first-generation drugs and in those for whom these drugs are contraindicated or poorly tolerated. As an exception, some new-generation drugs are a valuable option in the presence of comorbidities known to respond to these products or in patients with selected epilepsy syndromes. In light of the heterogeneity and the complexity of the mechanisms underlying epileptic seizures, the future of drug development will be the discovery of drugs efficacious for the treatment of selected epilepsy syndromes or, more specifically, targeting genetic defects leading to molecular abnormalities.     

Drug selection for the newly diagnosed patient: When is a new generation antiepileptic drug indicated?

Abstract. Treatment options in epilepsy have increased dramatically since the early 1990s with the introduction of nine new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). This makes drug selection much more complicated and challenging. This review discusses drug selection in patients with newly diagnosed epilepsy and in particular the role of new AEDs in this population. The choice of treatment should always be based on a careful comparison of the risk-benefit ratio for the different treatment options and the outcome of such evaluation may be different in patients with new onset compared with chronic epilepsy. Efficacy, tolerability and safety are the main criteria for selection of AEDs and any first line drug for patients with newly diagnosed epilepsy must have demonstrated satisfactory efficacy as monotherapy in that patient population. So far, of the new AEDs only lamotrigine, oxcarbazepine and topiramate have documentation sufficient to be granted licence for use as monotherapy in most European countries. Because the new generation AEDs have failed to demonstrate improved effectiveness as monotherapy, old generation AEDs such as carbamazepine and valproate remain drugs of first choice for partial and generalised seizures, respectively. However, there are special situations and populations where a new AED may be a reasonable first line drug. These include vigabatrin in West syndrome associated with tuberous sclerosis, lamotrigine as alternative to valproate in idiopathic generalised seizures in women of childbearing potential and lamotrigine for the treatment of epilepsy in the elderly population. The role of the new generation AEDs is likely to become more prominent as more experience is gained.     

New antiepileptic drugs in pediatric epilepsy

New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy.     

Epilepsy and pregnancy.

The management of the pregnant epileptic requires close cooperation between the neurologist and obstetrician. To prevent complications, knowledge is required about the natural history of epilepsy during pregnancy, the possible teratogenic effects of antiepileptic drugs, and changes in their absorption, biotransformation, and excretion. Close plasma antiepileptic drug monitoring is required because of the change in the handling of antiepileptic drugs during pregnancy. The treatment of status epilepticus with intravenous phenytoin is effective. Drug interactions which may lead to toxic plasma levels of some drugs and subtherapeutic plasma levels of others should be anticipated. The risk of problems resulting from antiepileptic drug therapy during pregnancy appears to be minor, provided that proper medical supervision is available. Newer antiepileptic drugs should not be administered to the pregnant epileptic until their safety in pregnancy is fully established.     

Effect of anti-epileptic drug therapy on the unborn child

Antiepileptic drugs have been shown to be teratogenic, affect children’s physical development and have neurodevelopmental effects. These drug-related effects are part of the major burden of epilepsy. Individual drugs need to be assessed via prospective studies, possible only by using pregnancy registers complying with ethical guidelines. Monotherapy data indicate valproate to be the most teratogenic drug, although it is the most effective drug and its teratogenicity is dose-related. To the author’s knowledge no specific malformations have clearly been proven to be attributable to a specific drug with the exception of valproate. Other antiepileptic drugs appear to be mildly teratogenic and newer drugs are possibly safer. A balance must be achieved between efficacy and teratogenicity. An outline is given of the problems of seizure control, polytherapy issues and lack of specific malformations ascribed to any individual drugs, and a brief reference to cognitive changes is presented.     

Pharmacologic treatment of intractable epilepsy in children: a syndrome-based approach

The successful pharmacologic treatment of intractable childhood epilepsy is predicated upon an accurate classification of the epilepsy syndrome. The selection of an antiepileptic drug is facilitated by the knowledge of syndrome-specific efficacy, the anticipation of potential side effects, and a careful risk-benefit assessment tailored to each patient. As such, the identification of comorbidities and careful monitoring for treatment-emergent adverse events, especially cognitive and behavioral effects, is of utmost importance. Especially in refractory cases, polypharmacy may increase the likelihood of side effects, but carefully chosen combinations can result in synergistic benefit. For most epilepsy syndromes, newer antiepileptic drugs typically yield equivalent efficacy and superior tolerability. Nevertheless, continued research is needed to further contrast the syndrome-specific efficacy and tolerability of available drugs and to foster the development of new agents with superior efficacy and side effect profiles.     

Primary prevention of epilepsy in patients with different epileptogenic conditions

Epileptic seizures are a common complication of several clinical conditions affecting the CNS. In these cases, the occurrence of seizures and epilepsy may increase the functional damage provoked by the underlying epileptogenic condition and affect the patient's quality of life to a significant extent. Therefore, the search of effective means for primary prevention of seizures and epilepsy is necessary in these cases. However, the use of antiepileptic drugs for the primary prevention of seizures and epilepsy can be considered only if the ratio between efficacy, safety and tolerability of treatment is favorable, in that the advantages, in terms of seizure prevention, outweigh the disadvantages in terms of adverse effects and overall costs of treatment. In this article, the efficacy, safety and tolerability of antiepileptic drugs for the primary prevention of seizures and epilepsy are reviewed. The areas covered include: the definition of early (provoked) and late (unprovoked) seizures; knowledge of the overall risk of seizures and epilepsy in CNS disorders for which primary prevention of seizures can be attempted; rationale for the use of antiepileptic drugs for the primary prevention of epilepsy; experimental data on the antiepileptogenic properties of antiepileptic drugs; available literature findings on the prevention of early and late seizures, with specific emphasis on randomized clinical trials; and the main problems with experimental trials for the primary prevention of epileptic seizures. On this basis, practice recommendations for the primary prevention of epilepsy will be offered where indicated. Suggestions for future research are also made as concluding remarks, by indicating the areas of investigation and the design of future studies.     

Treatment of epilepsy in adults. Options and strategies

Currently, epilepsy can be treated with antiepileptic drugs and, in patients with focal and/or secondarily generalized seizures (focal epilepsy), by means of surgery and vagus nerve stimulation. In the choice of monotherapy possible negative drug related effects on cognitive, endocrine, and psychic symptoms must be considered. Newly developed antiepileptic drugs help to establish an individualized strategy, especially in antiepileptic drug monotherapy. Additionally these antiepileptic drugs have proven to be effective and well tolerated when combined with other antiepileptic drugs. Surgery of focal epilepsy offers the chance of complete cure. Vagus nerve stimulation is a nonmedical treatment option used in addition to antiepileptic drugs in patients with focal epilepsy. Tolerability and safety data should be considered to establish a long-term medical treatment tolerated and accepted by the patient.     

Adverse effects of antiepileptic drugs

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects.     

Antikonvulsive Pharmakotherapie Jugendlicher und Erwachsener

In spite of the introduction and improvement especially of epilepsy surgery and also of other treatment options, such as ketogenic diet or neurostimulation, anticonvulsant chronic drug treatment has clearly remained the standard for the vast majority of epilepsy patients. Since 1992 when the first antiepileptic drug (AED) of the newer generation was introduced, a marked increase of seizure freedom among epilepsy patients, which is still the primary goal of treatment, has, however, not been reached. However, some of the new AEDs potentially allow better tolerable long-term treatment due to superior pharmacological characteristics. This might help to address the aspect of chronic AED treatment or comorbidities more efficiently. Hence, tolerability reasons led to a ranking according to the guidelines of the German Neurological Society that recommend lamotrigine and levetiracetam as first-line AEDs in cases of focal epileptogenesis. Special individual needs and considerations may allow and justify other AEDs in certain patients who are labelled for monotherapy. In cases of generalized epileptogenesis in adults valproic acid remains the first-line AED but lamotrigine may be preferred in special circumstances which include aspects such as teratogenicity. Ethosuximide is a first-line AED together with valproic acid followed by lamotrigine. If bilateral convulsive seizures occur primidone and phenobarbital may be considered as third-line AEDs. Several experts prefer levetiracetam although it is labelled only for off-label treatment in juvenile myoclonic epilepsy and not as monotherapy. The latter, however, should remain state of the art, as it more practicable and the easiest to assess concerning effectiveness. If treatment fails in spite of a correct diagnosis and classification an alternative monotherapy should be considered although a variety of publications have indicated that in the era of new AEDs combinations may be necessary to achieve sustained freedom of seizures. Thus the necessity to obtain alternative monotherapies should probably be expressed less dogmatically than currently published in the guidelines. Combinations should be as simple as possible and be comprehensible concerning the individual impact of the combination partners. High efficacy, lack of interactions and good tolerability have made levetiracetam to the most important add-on drug beyond the well-established and supra-additive combination of valproic acid and lamotrigine. Further investigations must be carried out on whether the latest new AEDs lacosamide, retigabine and perampanel all offer new modes of action with benefits for patients and opening the door to a more rational polytherapy in epilepsy treatment. Currently similar efficacy suggests that the risk of clinically relevant interactions and tolerability is the most important factor when choosing the appropriate add-on drug. Discontinuation may be considered only after freedom of seizures for many years and the prognosis is most favorable when the major causative factor no longer exists or has been eliminated.     

New Horizons in the development of antiepileptic drugs: Innovative strategies

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or the underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma or stroke. Thus, there are at least four important goals for the future: (1) development of better antiepileptic ("anti-ictal") drugs with higher efficacy and tolerability to stop seizures compared to current medications; (2) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (3) development of disease-modifying therapies, interfering with progression of epilepsy, and (4) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The third Workshop on New Horizons in the Development of Antiepileptic Drugs explored these four goals for improved epilepsy therapy, with a focus on innovative strategies in the search for better anti-ictal drugs, for novel drugs for prevention of epilepsy or its progression, and for drugs overcoming drug resistance in epilepsy. In this conference review, the current status of antiepileptic therapies under development is critically assessed, and innovative approaches for future therapies are highlighted.