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 epilepsy in children.     

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.     

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.     

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.     

Eslicarbazepine acetate: a new option for the treatment of focal epilepsy

Background: Epilepsy is a neurological condition with an increased probability of seizure occurrence through time. Although many anti-epileptic drugs (AEDs) exist, they fail to treat seizures in 30% of patients with epilepsy. For these patients, new AEDs potentially more efficacious and safe are developed. Objective: To evaluate the effectiveness of eslicarbazepine acetate (ESL) in the treatment of patients with refractory epilepsy. Methods: A review of the literature was carried out using PubMed central. A direct contact with the drug manufacturer and developer was made. Results/conclusion: ESL is an AED that acts by inhibiting voltage-gated sodium channels. It has proved efficacious in the treatment of patients with refractory focal-onset epilepsy with a good safety profile. Evaluation of its use for treating other epileptic syndromes and its role as an initial treatment option for patients with epilepsy is warranted.     

Pharmacotherapy of the third-generation AEDs: lacosamide,retigabine and eslicarbazepine acetate

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults.

Areas covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug–drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper.

Expert opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug–drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.     

New anti-seizure medication for elderly epileptic patients

ABSTRACT

Introduction: Epilepsy treatment in older people requires specific consideration owing to more physical co-morbidities, the risk of drug-to-drug interactions through polypharmacy, and differences in pharmacodynamics and pharmacokinetics. There are many ‘newer’ antiepileptic drugs (AEDs) widely used for various seizure types and seizure disorders. However, there is limited specific evidence for the efficacy, safety, and tolerability of these treatments in the elderly population.

Areas covered: This review summarises the current most robust evidence available for the use of the newer AEDs belonging to generation two and three in elderly people with epilepsy. The article provides practical evidenced based clinical information to help prescribers choose the most appropriate AED from the drugs discussed.

Expert opinion: Diagnosing new onset epilepsy in the elderly population requires specialist assessment. Treatment plans need to be tailored to accommodate an individual’s co-morbidities, concurrent medications, and general health status. To date, few clinical investigations consider the elderly population specifically despite the increased risk factors. There is a need for large quality trial data to assess the impact of the newest AEDs on seizure control and quality of life in this population with complex needs.     

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.     

A resurging boom in new drugs for epilepsy and brain disorders

Introduction: Epilepsy is one of the most common neurological diseases affecting approximately 50 million people worldwide. Despite many advances in epilepsy research, nearly a third of patients with epilepsy have refractory or pharmacoresistant epilepsy. Despite the approval of a dozen antiepileptic drugs (AEDs) over the past decade, there are no agents that halt the development of epilepsy. Thus, newer and better AEDs that can prevent refractory seizures and modify the disease are needed for curing epilepsy.

Areas covered: In this article, we highlight the recent advances and emerging trends in new and innovative drugs for epilepsy and seizure disorders. We review in detail top new drugs that are currently in clinical trials or agents that are under development and have novel mechanisms of action.

Expert commentary: Among the new agents under clinical investigation, the majority were originally developed for treating other neurological diseases (everolimus, fenfluramine, nalutozan, bumetanide, and valnoctamide); several have mechanisms of action similar to those of conventional AEDs (AP, ganaxolone, and YKP3089); and some new agents represent novel mechanisms of actions (huperzine-A, cannabidiol, tonabersat, and VX-765).     

Sexual dysfunction related to antiepileptic drugs in patients with epilepsy

Introduction: Epilepsy is a common disease that is mostly treated with antiepileptic drugs (AEDs). However, the sexual dysfunction (SD) side effects related to the use of AEDs have not received sufficient attention.

Areas covered: The purpose of this review is to examine the current evidence on SD-related side effects of AEDs. The incidence, clinical features and major types of SD are summarized. Furthermore, various AEDs that may cause SDs are addressed in detail. Finally, we briefly summarize the treatments for SD related to AEDs.

Expert opinion: SD related to AEDs is common. Symptoms include erectile dysfunction (ED), hyposexuality, hypersexuality and ejaculatory dysfunction. Traditional AEDs such as valproate and enzyme-inducing AEDs (EIAEDs) may produce high incidences of decreased libido. Recently, sexual function changes related to new AEDs have been reported. Topiramate, pregabalin and gabapentin may cause SD, whereas oxcarbazepine, lamotrigine and levetiracetam may improve sexual function. Although the treatment for SD related to AEDs remains unclear, switching to another AED may be an option. Further studies are necessary to better understand and treat SD related to AEDs.     

癫癎治疗中值得关注的问题

探讨癫痫治疗过程中可能遇到的、值得注意的问题。如癫痫的预防性治疗、第一次发作是否治疗、药物之间的选择及相互作用、药物治疗原则等，并对药物抵抗性癫痫、药物性癫痫、药物和妊娠、药物的监测等进行了讨论。明确发作类型，选择合适的药物，首选单药治疗，应用最小的剂量，达到最大程度的控制及最小的不良反应，是治疗成功的关键。     

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.     

Bone loss associated with use of antiepileptic drugs

Importance of the field: Epilepsy is a neurological disorder associated with several comorbidities, one of them being reduced bone health. As the bone loss most often is insidious and asymptomatic, they are usually not recognized, and thus untreated. The key message of this paper is to make clinicians aware of the problem.

Areas covered in this review: This article reviews data from basic and clinical studies of bone loss associated with usage of antiepileptic drugs (AEDs) within the last 4 decades.

What the reader will gain: The reader will learn that there is accumulating evidence of biochemical abnormalities indicating a disturbed bone metabolism, a decreased bone density and a 2 – 6 times increased risk of fractures among those with epilepsy compared to the general population. These findings most likely have many causes, both internal and external, but long-term use of AEDs seems to play an important role. Enzyme-inducing drugs, such as phenytoin, phenobarbital and carbamazepine, but also the enzyme inhibitor valproate, appear to have bone-depleting properties. Reduced bone density may be detected during the first 1 – 5 years of treatment. Although many theories have been launched, the exact mechanisms by which the the drugs affect bone architecture are not fully understood.

Take home message: We recommend clinicians to promote osteoprotective behavior among their epilepsy patients; that is, sunlight exposure and weight-bearing exercise as well as avoidance of risk factors such as bone-depleting drugs other than AEDs, smoking and heavy alcohol consumption. Enzyme inducing drugs should be avoided, if possible. Bone mineral density screening should be assessed on an individual basis, taking risk factors for bone loss into account. All patients taking AEDs on long-term basis ought to have adequate amounts of dietary calcium and vitamin D, and those who have developed bone loss should in addition be given specific antiosteoporotic treatment.     

Investigational small molecules in phase II clinical trials for the treatment of epilepsy

ABSTRACT

Introduction: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.

Areas covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.

Expert opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find ‘superselective’ AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.     

Treatment strategies for focal epilepsy

Background: Treatment strategies for focal epilepsy need to take account of the phase and severity of the seizure disorder, comorbidity, gender and age. Methods: Expert review and evaluation of major studies on the treatment of focal epilepsy. Results: Complete seizure control is most often achieved with antiepileptic drug (AED) monotherapy. In the choice of AED, possible unfavourable endocrine, cognitive or psychiatric adverse effects and their interaction with the non-seizure manifestations of focal epilepsy have to be considered. In women teratogenic risks associated with AED may be relevant. If complete seizure control cannot be achieved with the first three steps of AED treatment, epilepsy surgery becomes the most likely treatment modality to provide complete seizure control. It is proposed that AED combination treatment should be limited to two or three agents to minimize the risk of side effects, especially negative effects on cognition. Conclusions: Recent developments in the treatment of focal epilepsy have made it easier to tailor AED therapy to patients' demographic and clinical profile.     

Zonisamide in the treatment of epilepsy

Importance of the field: More than 1 million epilepsy patients suffer from insufficiently controlled epilepsy, both in the USA and in Europe. Zonisamide is an antiepileptic drug with multiple mechanisms of action, corresponding to efficacy in diverse epilepsy syndromes.

Areas covered in this review: Here, an update on pharmacodynamics, pharmacokinetics, clinical efficacy and safety in childhood and adult epilepsies is given based on an analysis of controlled and uncontrolled studies, European, US and East Asian, and on clinical experience with zonisamide (ZNS) published up to 2009.

What the reader will gain: Evidence is presented that ZNS is effective not only in adult focal epilepsies, for which it has been approved in the USA and in Europe, but also may offer treatment options for compassionate use in a spectrum of difficult-to-treat epilepsy syndromes. Its favorable pharmacokinetic profile allows for easy combination with most available antiepileptic drugs.

Take home message: Provided that additional studies on ZNS are performed to extend approval and to generate comparative data, ZNS has a potential to gain importance in the treatmnt of a wide spectrum of epilepsy patients.     

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.     

Relative performance of brivaracetam as adjunctive treatment of focal seizures in adults: a network meta-analysis

Objective: To estimate the relative efficacy, safety and tolerability of adjunctive brivaracetam and other antiepileptic drugs (AEDs) using a Bayesian network meta-analysis (NMA) approach.

Methods: A systematic literature review (SLR) identified randomized controlled trials of AEDs treating focal (partial-onset) seizures for ≥8 weeks and assessed them for inclusion in the NMA. Bayesian random-effects NMA was performed for several outcomes. All interventions within the licensed dose range were included in the network of evidence.

Results: The SLR identified 82 studies; 65 were included in the NMA. These studies had baseline mean age 33.1–38.0 years, mean duration of epilepsy 18.7–23.0 years and median seizure frequency/28 days 8.1–11.8. All AEDs had significantly higher odds than placebo of achieving ≥50% responder rates (odds ratios 1.83–3.58) and all AEDs had a trend of higher odds than placebo of achieving seizure freedom (odds ratios 1.36–5.73), most being statistically significant. Tolerability outcomes were comparable between AEDs; most AEDs had higher odds than placebo of treatment-emergent adverse events leading to discontinuation, serious AEs, nausea, fatigue, dizziness and somnolence.

Conclusions: This NMA would appear to show relative equivalence in efficacy, safety and tolerability outcomes of the included AEDs. However, patient heterogeneity within trials and in clinical practice should be considered when interpreting these results. While NMAs are based on the best available evidence the authors suggest that, due to the inability of NMAs to capture unmeasured confounding factors and population heterogeneity, NMAs must not be the sole basis for comparative treatment recommendations.     

Epilepsy drug review: patent activity from 1999 to 2002

This article summarises the patent activity in the anticonvulsant field for the period 1999 – 2002. Since numerous patents include treatment of epilepsy among their utility claims without direct supporting evidence, the authors have limited the discussion to applications which present efficacy data in one or more animal seizure models or to mechanisms of action for which there is ample literature evidence to support the claims. The various patents are grouped into common mechanistic themes, with additional sections provided for agents which resemble or are derived from known marketed antiepileptic drugs (AEDs) and for agents which act via unknown mechanisms. A summary of patenting trends and a discussion of the overall impact of patenting activity for this period are provided.     

Pharmacovigilance in psychiatry: pharmacogenetic tests and therapeutic drug monitoring are promising tools

Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. This article briefly describes the pharmacokinetic interactions between antiepileptic drugs (AEDs) and hormonal contraceptives and the rational strategies that may overcome these risks. Hormonal contraception, including the use of oral contraceptives (OCs), is widely used in many women with epilepsy – there is no strong evidence of seizures worsening with their use. AEDs are the mainstay for seizure control in women with epilepsy. However, there are many factors to consider in the choice of AED therapy and hormonal contraception, since some AEDs can reduce the efficacy of OCs owing to pharmacokinetic interactions. Estrogens and progestogens are metabolized by cytochrome P450 3A4. AEDs, such as phenytoin, phenobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and primidone, induce cytochrome P450 3A4, leading to enhanced metabolism of either or both the estrogenic and progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. OCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. Increased awareness of AED interactions may help optimize seizure therapy in women with epilepsy.