Pharmacotherapy for children and adolescents with epilepsy

Introduction: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25 – 30% of children with epilepsy remain refractory to medical therapy.

Areas covered: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability.

Expert opinion: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and – subsequently – as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilspsy in children.     

Zonisamide in the treatment of epilepsy

Introduction: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs.

Areas covered: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide.

Expert opinion: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

Brivaracetam for the treatment of epilepsy

Introduction: Epilepsy is one of the most common neurological disorders, affecting about 1% of the population worldwide. With currently available antiepileptic drugs, one-third of patients continue to suffer from seizures even when treated at maximally tolerated dosages, either in monotherapy or in various drug combinations. Pharmacoresistance is associated with physical risks, reduced life expectancy, reduced quality of life and impairments in social opportunities. The acetamide derivate levetiracetam (LEV) that primarily targets the synaptic vesicle protein 2A has been one of the most successful second-generation antiepileptic drugs.

Areas covered: This article reviews a rationally designed LEV derivative, brivaracetam (BRV), which has an increased affinity to the LEV-binding site. BRV has shown some efficacy in the treatment of progressive myoclonus epilepsy and is under development to be used as an add-on treatment of focal epilepsy. Evidence is given for possible advantages related to the higher intrinsic antiepileptic efficacy of BRV and its antiepileptic potential in relation to a wide spectrum of epilepsy forms and for possible disadvantages related to hepatic metabolism and to a lower therapeutic index related to additional intrinsic activity at the sodium channel. An update on pharmacodynamic, pharmacokinetic and study data published until 2010 on BRV is given.

Expert opinion: BRV is a rationally developed third-generation antiepileptic drug with higher binding to SV2A and additional mechanisms of actions. Animal studies are promising regarding its efficacy in a wide spectrum of epilepsy models. Clinical studies have shown good tolerability at dosages of up to 50 mg/day but have yet to identify the optimal dose range and to prove an additional value of the drug in terms of seizure control.     

Pharmacotherapy for tonic–clonic seizures

Introduction: Occurrence of generalized tonic–clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies.

Areas covered: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used.

Expert opinion: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.     

Advancing pharmacologic treatment options for pharmacologic treatment options for children with epilepsy

Introduction: The pharmacological management of epilepsy is continually modified by the increase in our knowledge about the efficacy and the safety on antiepileptic drugs.

Areas covered: This review covers the published data (2010–2015) on the pharmacological management of epilepsy in children and adolescent. We review the data from the most recent randomized controlled and open-label trials.

Expert opinion: Even if there is an increasing number of antiepileptic drugs approved for focal seizure in children and adolescent with epilepsy, each new approval would be considered as a significant addition to the current therapeutic options. Refractory epilepsy with focal seizure should not be regarded as a single disease but as numerous various patients. Because most of evidence of efficacy is primarily from placebo-controlled trials, there is no evidence to choose a treatment based on efficacy. In case of focal seizure, we explain how possible cognitive impact, mechanisms of action, pharmacologic characteristics and side effect profile are the factors taken into an account to propose a treatment. In case of childhood absence epilepsy, there are evidences showing the ethosuximide should be the first line treatment. Finally, we stress that trials in the pediatric epilepsy syndromes are required to propose better evidence-based pharmacological management.     

Extended-release lamotrigine in the treatment of patients with epilepsy

Importance to the field: Epilepsy is a neurological disorder primarily characterized by recurrent, unprovoked seizures resulting from excessive or synchronous neuronal activity in the brain. Depending on the case definition and population studied, the lifetime prevalence of epilepsy in the USA is estimated to be 1.2 – 2.9%. In general, epilepsy is related to a significant increased risk of mortality and injury. A cornerstone of epilepsy management is use of antiepileptic drugs (AEDs). This review focuses on the AED lamotrigine, with particular emphasis on the extended-release formulation, in the management of patients with epilepsy, and the significant clinical issues that may be relevant with once-daily AED therapy.

Areas covered in this review: An introductory section overviews the prevalence of epilepsy, current treatment recommendations for patients with epilepsy, and unmet needs in epilepsy management. This is followed by an overview of the AED market with currently available and developing compounds, a summary of lamotrigine and extended-release lamotrigine, clinical efficacy and tolerability studies with extended-release lamotrigine, and regulatory issues. The review concludes with an expert opinion summary on the important issue of treatment adherence, the possible role of extended-release lamotrigine in adherence enhancement, and additional research and areas which need further focus for optimal epilepsy outcomes.

What the reader will gain: The reader will gain familiarity with extended-release (once-daily) lamotrigine and clinical issues that may be relevant to once-daily use. Once-daily AED use might be one way to simplify the epilepsy treatment regimen and can pave the way for other approaches that can maximize adherence, such as a frank discussion of risks, benefits, and attitudes towards treatment – all critical components of a strong and positive doctor–patient relationship.

Take home message: The AED lamotrigine is widely used in clinical settings and has become available in a once-daily extended-release version, which may minimize serum concentration fluctuation and presumably would both reduce patient burden and maximize treatment adherence as opposed to the immediate-release version of the compound. Adverse effects and safety concerns between the immediate- and extended-release versions of lamotrigine seem similar based upon interpretation of the limited literature.     

Emerging drugs for partial onset seizures

Importance of the field: Patients with epilepsy have recurrent unproved seizures. Epilepsy is common, with a prevalence range that centers at around 1%. Patients with epilepsy can have a poor quality of life and suffer significant social stigma. Despite the availability of a large number of antiepileptic drugs (AEDs) including standard and newer ones, a significant percentage of patients with epilepsy remain poorly controlled.

Areas covered in this review: In this review, we briefly summarize data on the available AEDs, then present current information on the emerging AEDs, including their chemical structure, pharmacology, mechanism of action, and efficacy and adverse event profile in clinical trials. The AEDs included are rufinamide, lacosamide, eslicarbazepine, retigabine, brivaracetam, ganaxolone, stiripentol and carisbamate. Most of the literature related to these AEDs was published in the past 5 years.

What the reader will gain: The reader will become familiar with the pharmacology of emerging AEDs and the results of clinical trials with these AEDs. The reader will also be able to assess the advantages of AEDs and their potential respective places in the treatment of epilepsy.

Take home message: The emerging AEDs offer predominantly improved pharmacokinetics and tolerability and occasionally new mechanisms of action. They will probably have a modest impact on drug-resistant epilepsy.     

Lacosamide: new adjunctive treatment option for partial-onset seizures

Importance of the field: Epilepsy is one of the most common neurological disorders, affecting up to 2% of the population worldwide. Studies show that patients with refractory seizures have higher morbidity and mortality rates, as well as a poorer quality of life, than those with controlled seizures. Therefore, treatment that reduces the frequency of seizures may improve patients' quality of life. Lacosamide (LCM) is a recently approved anticonvulsant in Europe and the USA which offers new mechanisms of action and favorable safety profiles. Efficacy data have shown fast onset of anticonvulsant effects and significant reduction of partial-onset seizures as adjunctive therapy at LCM 200 and 400 mg/day, even in a severely refractory population.

Areas covered in this review: This article reviews three pivotal clinical trials of LCM, including its efficacy and tolerability over 7 years. In addition, LCM's key pharmacodynamics and pharmacokinetics from a search of the literature are reviewed in detail. This article also includes recent publications on the safety and use of intravenous LCM solution for patients with epilepsy.

What the reader will gain: This article provides comprehensive review of efficacy and safety information of LCM along with comprehensive pharmacokinetic information, which includes absolute bioavailability, low protein binding, lack of hepatic enzyme induction or inhibition, and low potential for drug-drug interactions.

Take home message: Considering the fact that more than 30% of epilepsy patients remain refractory despite various antiepileptic drugs, LCM may provide added benefit to patients with refractory seizures.     

Pharmacological considerations in the use of stiripentol for the treatment of epilepsy

Introduction: Despite the fact that more than 20 antiepileptic drugs (AEDs) are currently available, about one-third of patients still present drug resistance. Further efforts are required to develop novel and more efficacious therapeutic strategies, especially for refractory epileptic syndromes showing few and anecdotic therapeutic options.

Areas covered: Stiripentol (STP) is a second generation AED that shows GABAergic activity, with immature brain selectivity, and an indirect metabolic action on co-administered AEDs. Two pivotal studies demonstrated STP efficacy in patients with Dravet syndrome with refractory partial seizures, and marketing authorization in Europe, Canada and Japan was granted thereafter. Post-marketing surveys reported a good efficacy and tolerability profile. In addition, interesting data is currently emerging regarding off-label experimentation of STP in other forms of epilepsy.

Expert opinion: STP is an important addition to the limited treatment options available for patients resistant to common AEDs. The possibility to inhibit seizures through the metabolic pathway of lactate dehydrogenase and the inhibitory effects on the entry of Na⁺ and Ca²⁺ are the most recent findings to emerge about STP and could be proof of its neuroprotective action. Moreover, its positive effects on cognitive function, its good safety and tolerability profile and the increasing data about STP efficacy on other refractory epileptic syndromes may prove to be fertile grounds for further investigation.     

Lacosamide in patients with pharmacoresistant epilepsy

Introduction: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures.

Areas covered: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population.

Expert opinion: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.     

Pharmacokinetic/pharmacodynamic considerations for epilepsy – depression comorbidities

Introduction: Epilepsy may be frequently associated with psychiatric disorders and its co-existence with depression usually results in the reduced quality of life of patients with epilepsy. Also, the efficacy of antiepileptic treatment in depressed patients with epilepsy may be significantly reduced.

Areas covered: Results of experimental studies indicate that antidepressants co-administered with antiepileptic drugs may either increase their anticonvulsant activity, remain neutral or decrease the protective action of antiepileptic drugs in models of seizures. Apart from purely pharmacodynamic interactions, pharmacokinetic mechanisms have been proven to contribute to the final outcome. We report on clinical data regarding the pharmacokinetic interactions of enzyme-inducing antiepileptic drugs with various antidepressants, whose plasma concentration may be significantly reduced. On the other hand, antidepressants (especially selective serotonin reuptake inhibitors) may influence the metabolism of antiepileptics, in many cases resulting in the elevation of plasma concentration of antiepileptic drugs.

Expert opinion: The preclinical data may provide valuable clues on how to combine these two groups of drugs – antidepressant drugs neutral or potentiating the anticonvulsant action of antiepileptics are recommended in this regard. Avoidance of antidepressants clearly decreasing the convulsive threshold or decreasing the anticonvulsant efficacy of antiepileptic drugs (f.e. bupropion or mianserin) in patients with epilepsy is recommended.     

Treatment of idiopathic generalized epilepsy – a review of the evidence

Introduction: Epilepsy is stratified into idiopathic partial, symptomatic partial, idiopathic generalized (IGE) and symptomatic generalized epilepsies.

Areas covered: The epidemiology and clinical characteristics of IGE are reviewed in this paper. Clinically, IGE is characterized by the occurrence of any of the following three seizure types: absence seizures, myoclonic seizures and primarily generalized tonic-clonic seizures. To assess the presence of evidence-based data on the treatment of IGE, the literature was extensively reviewed for studies evaluating the treatment of IGE with various antiepileptic drugs. These studies were stratified into four classes based on recently described criteria. Class I studies were considered as providing evidence of the efficacy of the drug in patients with IGE. Finally, suggestions to evaluate the efficacy of a study drug in patients with IGE are presented.

Expert opinion: Based on the reviewed data, there is strong evidence-based data to support the use of valproate and ethosuximide for the treatment of childhood absence seizures; for the use of topiramate as monotherapy or adjunctive therapy for patients with primarily generalized tonic-clonic seizures; for the use of adjunctive therapy with lamotrigine for the treatment of primarily generalized tonic-clonic seizures; and for the use of levetiracetam as adjunctive therapy for the treatment of myoclonic or primarily generalized tonic-clonic seizures. To evaluate a new drug as a potential treatment for patients with IGE requires a rational methodology, discussed in this review.     

Novel approaches to anticonvulsant drug discovery

Introduction: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine).

Areas covered: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs.

Expert opinion: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs – ones that can effectively modify the course of the disease.     

Update on pharmacotherapy of myoclonic seizures

Introduction: Myoclonic seizures are brief, involuntary muscular jerks arising from the central nervous system that can occur in different epilepsy syndromes, including idiopathic generalized epilepsies or the most severe group of epileptic encephalopathies. Valproate is commonly the first choice alone or in combination with some benzodiazepines or levetiracetam. However, more treatment options exist today as there is emerging evidence to support the efficacy of some newer antiepileptic drugs. In addition, of major importance remains avoidance of medications (e.g., carbamazepine, phenytoin) that may aggravate myoclonic seizures. This is an updated review on the available therapeutic options for treatment of myoclonic seizures.

Areas covered: Key efficacy, tolerability and efficacy data are showed for different antiepileptic drugs with antimyoclonic effect, alone and/or in combination.

Expert opinion: Pharmacological treatment of myoclonic seizures is based on clinical experience with little evidence from randomized clinical trials. Valproate, levetiracetam, and some benzodiazepines, are widely used. There is still insufficient evidence for the use of other antiseizure drugs, such as topiramate or zonisamide as monotherapy. Better understanding of pathophysiologic mechanisms of myoclonic epilepsies could yield great improvement in the treatment and quality of life of patients.     

Computational approaches for innovative antiepileptic drug discovery

ABSTRACT

Introduction: Despite the approval of a large number of antiepileptic agents over the past 25 years, there has been no significant improvement in efficacy of treatments, with one third of patients suffering from intractable epilepsy. This scenario has prompted the search for innovative drug discovery solutions. While network pharmacology and explanations of the drug resistance phenomena have been proposed to drive the search for more efficacious therapeutic solutions, such alternative approaches have not fully taken hold within the antiepileptic drug discovery community so far.

Areas covered: Herein, the author discusses the impact that network pharmacology and the current hypotheses of refractory epilepsy and drug repurposing could have if integrated with anti-epileptic computer-aided discovery.

Expert opinion: With many complex diseases, the advancement in the understanding of disorder pathophysiology in addition to the contribution of systems biology have rapidly translated into the discovery of novel drug candidates. However, antiepileptic drug developers have fallen a little behind in this regard, with fewer examples of computer-aided antiepileptic drug design and network-based approximations appearing in scientific literature. New generation single-target agents have so far shown limited success in terms of enhanced efficacy; in contrast, multi-target agents could possibly demonstrate improved safety and efficacy.     

Adjunctive antiepileptic drugs in adult epilepsy: how the first add-on could be the last

Importance of the field: In adult epilepsies, incomplete seizure control under monotherapy affects ～ 20 – 25% of patients with idiopathic generalized epilepsies (IGE) and ～ 20 – 40% of patients with epilepsies with focal seizures (FE). The choice of an adjunctive therapy is therefore a common event.

Areas covered in this review: Efficacy studies of add-on anti-epileptic drugs for adult epilepsies – approved since the early 1990s until 2008 – were reviewed. An exception was made for valproate.

What the reader will gain: Efficacy studies give important clues for add-on drug choice but – beyond this – we encourage physicians to consider other parameters, especially co-morbidity(ies) and special situation(s). According to clinical and pharmacological data, an original, practical approach is proposed, by which decisions are based on three main criteria, which aim to optimize patients' seizure control and quality of life. The need for drugs that act not only on ‘ictogenesis’ but also on ‘epileptogenesis’ is also discussed briefly.

Take home message: Given the increasing disposal of anti-epileptic drugs, the choice of an add-on therapy appears to be partly based on subjective criteria (physician opinions and preferences). In fact, the selection criteria can be clarified as: treatment decisions rely not only on seizure type, efficacy and tolerability profiles but also on patient-related factors.     

Pharmacotherapy of idiopathic generalized epilepsies

Background: Idiopathic generalized epilepsies (IGE) represent about 20% of all epilepsies, are genetically determined and comprise several subgroups of syndromes. Although complete seizure control is achievable in about 80% of patients with IGE syndromes, a substantial group remains with inadequate control and unsatisfactory long-term outcome. Several new antiepileptic drugs (AEDs) have been studied in children with IGE. Objectives and Methods: To review the rational drug choice for these patients, the PubMed database was searched with the keywords IGE and AEDs. Results: Older AEDs continue to play a major role in the treatment of IGE. Although the first line monotherapy is still with sodium valproate, new drugs like lamotrigine, levetiracetam and topiramate, are increasingly used in the treatment of IGE. Conclusions: Further research on evidence-based treatment of IGE with new AEDs is needed. New data from molecular genetics of IGE might have the potential to help clinicians choose the most appropriate antiepileptic therapy.     

Treating myoclonic epilepsy in children: state-of-the-art

Introduction: Myoclonic seizures can be observed in various clinical settings and different epileptic conditions, including some forms of both diopathic and symptomatic epilepsies. Relatively little has been written on treatment of myoclonic seizures. Some old antiepileptic drugs, such as valproate and some benzodiazepines, are widely used but more treatment options exist today for some newer antiepileptic drugs. Nevertheless, patients can be refractory to drug treatment and some drugs may exacerbate or even induce myoclonus.

Areas covered: Key safety, tolerability, and efficacy data are presented for different antiepileptic drugs with antimyoclonic effect, alone and/or in combination.

Expert opinion: Treatment of myoclonic seizures in children is mainly based on prospective and retrospective studies, with little evidence from randomized clinical trials. Valproate is commonly the first choice alone or in combination with some benzodiazepines or levetiracetam. There is still insufficient evidence for the use of topiramate and zonisamide as monotherapy. Of major importance remains avoidance of medication that may aggravate the seizures. Better understanding of pathophysiologic mechanisms of myoclonic seizures and myoclonic epilepsies could yield great improvement in the treatment and quality of life of patients.     

Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy

Introduction: The non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) – receptor antagonist perampanel (PER) was approved in 2015 for treatment of primary generalized tonic-clonic seizures (pGTCS). The aim of this narrative review is to summarize available data on pharmacological properties, efficacy and tolerability of PER in pGTCs.

Areas covered: Data sources included MEDLINE, EMBASE, Google Scholar and ClinicalTrials.gov, conference proceedings of the ILAE congresses and the most recent conference proceedings of the American Epilepsy Society (2013 to 2015).

Expert opinion: A placebo-controlled clinical phase III study including 164 patients (≥ 12 years) with pGTCS in idiopathic generalized epilepsies (IGE) demonstrated efficacy of PER in reducing pGTCS with good tolerability profile, and without aggravating absence seizures or myoclonic seizures. Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders. Co-administration of enzyme inducing antiepileptic drugs (AEDs) might decrease PER plasma levels and make dose adjustment necessary. A reduced efficacy of progesterone-containing oral contraceptives should be considered when administering PER to young women. There is lack of evidence on PER treatment in pregnancy. Although no teratogenic effects were observed in animal models, PER is not recommended for women of childbearing age without contraception.     

The pharmacological treatment of depression in adults with epilepsy

Background: Comorbid mood disorders may affect quality of life in people with epilepsy. Objective: To review available data on the use of antidepressant drugs in epilepsy taking into account major concerns that may be encountered by clinicians, namely pharmacokinetic interactions with antiepileptic medications and seizure aggravation. Results: Data on pharmacotherapy of depression in epilepsy are limited with no controlled clinical trials investigating efficacy and safety of antidepressants. Data on seizure risk come from psychiatric samples, thus limiting the general applicability to people with epilepsy. Conclusions: Antidepressant drug doses need to be used and adjusted according to individual clinical needs. Within the therapeutic range, the incidence of seizures in psychiatric populations is low for most antidepressants.