Pharmacotherapy of focal epilepsy

Introduction: Epilepsy is the most common neurological condition worldwide with significant psychosocial and physical morbidity. Its management requires expertise and good pharmacological knowledge of the available options.

Areas covered: This review covers the management of focal epilepsy addressing the common questions arising through the patients’ journey, including timing of starting initial treatment, monotherapy options, add-on treatment for refractory cases and withdrawal of medication during remission.

Expert opinion: Initiating anti-epileptic drug (AED) treatment requires assessment of patient preferences and of evidence of benefit and harm. Evidence of benefit will come primarily from randomised controlled trials, although in epilepsy, most trials are undertaken to inform regulatory decision and have important limitations for informing clinical decisions. Evidence about harm may come not only from randomised trials but also from other sources. Most patients will start treatment following a second focal seizure. Carbamazepine and lamotrigine are good initial monotherapy options. Newer AEDs have proof of efficacy as monotherapy but evidence is insufficient to recommend them as first-line treatments. For refractory cases, there are an increasing number of AEDs available, but evidence of efficacy is primarily from placebo-controlled trials, and there is no robust evidence to inform a choice among treatments.     

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.     

Moving beyond sodium valproate: choosing the right anti-epileptic drug in children

ABSTRACT

Introduction: Sodium valproate is a widely used anti-epileptic drug with a broad spectrum of activity and mechanism of action. It has consequently been the first-line drug for most seizure types in children for the past fifty years. A wide range of side effects come along with these exceptional properties, including teratogenicity and neuro-cognitive impairments in offspring. Therefore, epilepsy treatment in children and adolescents should be reassessed in light of newer antiepileptic drugs as well as a more targeted-approach with older drugs.

Areas covered: The authors review the main concerns of valproate use in terms of adverse effects on different systems and drug interactions. The current alternatives to valproate in absence, myoclonic, tonic-clonic and focal onset seizures in children/adolescents are also reviewed.

Expert opinion: There are several issues that research should address in antiepileptic therapy and in clinical studies with children, given the peculiarity of this population. Future perspectives in epilepsy therapy should now lead towards an individualized treatment.     

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.     

Rufinamide for the treatment of Lennox–Gastaut syndrome

Introduction: Lennox–Gastaut syndrome (LGS) is a severe treatment-resistant childhood-onset epilepsy. This review examines the role of the new drug rufinamide for the treatment of LGS.

Areas covered: MEDLINE and Google Scholar searches were undertaken. The pharmaceutical company was contacted for the latest information. LGS is characterized by the triad of diffuse slow spike–wave discharges in the electroencephalogram (EEG), learning disability (mental retardation) and frequent generalized seizures of multiple types, usually including tonic, atonic and atypical absence seizures. Felbamate, lamotrigine and topiramate have resulted in significant reductions in some seizure types, but no treatment has achieved acceptable seizure control in most patients. In a pivotal randomized, double-blind, placebo-controlled trial, the new drug rufinamide achieved significant improvements in seizure control in previously resistant subjects when added to up to three concomitant antiepileptic drugs. Open studies including patients with LGS have also demonstrated efficacy. These trials and a large open trial in adults and adolescents with partial seizures have revealed no serious adverse effects so far. The most common adverse events were fatigue/somnolence and vomiting. Rufinamide is of value in decreasing seizure frequency in LGS, but seizure freedom is seldom achieved. Although no serious adverse effects have been identified, the limited data available at present allow no firm conclusions to be drawn with regard to safety.

Expert opinion: The data support a role for rufinamide in treating LGS. However, more efforts are required to provide antiepileptic drugs for this treatment-resistant epilepsy syndrome. Rufinamide might also be of value in treating other forms of epilepsy.     

An evaluation of zonisamide,including its long-term efficacy,for the treatment of focal epilepsy

Introduction: About 70 million people worldwide are estimated to suffer from epilepsy. Despite a large variety of old and new antiepileptic drugs on the market, about 30% of people with epilepsy do not become seizure-free with medical treatment. This is a major individual and public health burden. Most of these difficult-to-treat patients are having focal seizures. Zonisamide is effective against focal seizures in adults and children and, thus, a therapeutic option for such patients. Its safety profile needs special attention.

Areas covered: Herein, the authors discuss the pharmacology, clinical efficacy and the adverse effects of zonisamide. The article is derived from clinical trial data, long-term studies, meta-analyses, review articles, text books, webpages, and official license information.

Expert opinion: Zonisamide has proven to be efficacious in focal epilepsy in children and adults, although it is not more effective than carbamazepine or other antiepileptic drugs. It is also effective in generalized epilepsy and in several other conditions of the CNS. Its safety profile may prevent it from becoming a first-line drug for focal epilepsy or any other indication.     

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.     

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.     

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.     

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.     

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.     

Pharmacologic treatment of status epilepticus

Introduction: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE.

Areas covered: Following a four-stage approach of SE (early, established, refractory and super-refractory), we present pharmacological treatment options and their clinical utility.

Expert opinion: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super-refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors’ preferences, patient factors such as age and comorbidity, and cause of SE, if identified.     

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.     

The safety of pharmacological treatment options for lupus nephritis

ABSTRACT

Introduction: The management of lupus nephritis (LN) has changed significantly over the last 10 years due to emerging evidence from large randomised clinical trials that produced good quality data and guided the formulation of two key concepts: the induction of remission and the maintenance phase of immunosuppressive therapy.

Areas covered: Optimizing cyclophosphamide and glucocorticoid regimens and the introduction of mycophenolate mofetil for proliferative and membranous LN has been pivotal. Nevertheless, concerns remain about treatment toxicity especially long term glucocorticoid use and exposure to cumulative cyclophosphamide doses. Here we discuss the conventional and newer pharmacological options for managing LN focusing on drug safety and toxicity issues.

Expert opinion: The need for effective and less toxic treatments led to the development of the role of targeted biologic therapies in LN. However, evidence from the initial randomized controlled trials has been disappointing, although this reflects inadequate trial design rather than true lack of efficacy.     

Current and emerging pharmacologic options for the management of patients with chronic and acute decompensated heart failure

Introduction: For many years heart failure (HF) was known as a fatal disease with an ominous prognosis. In the last decades better understanding of the pathophysiological mechanisms underlying HF has resulted in major breakthrough in the management and improvement in the natural history of this clinical syndrome.

Areas covered: The review is focused on current and upcoming pharmacological therapies in patients with chronic and acute HF, starting with brief overview of drugs which improve the outcomes in patients with chronic HF with reduced ejection fraction (EF) including neurohormonal antagonists, angiotensin receptor neprilysin inhibitor and If- channel inhibitor, then presenting the summary of symptomatic treatment, the pharmacotherapy in chronic HF with preserved and mid-range EF and in acute HF. Finally, we report the emerging pharmacologic options and ongoing clinical trials and future directions in pharmacotherapy.

Expert commentary: The guidelines-recommended therapies in HF with reduced EF need to be widely implemented into the everyday clinical practice. Better clinical characterization of HF with preserved, mid-range EF and acute HF, with better understanding of the underlying pathophysiological mechanisms may ultimately result in a development of effective strategies improving ominous outcomes in these patients.     

Emerging drugs for the treatment of Dravet syndrome

ABSTRACT

Introduction: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment.

Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil, and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS.

Expert opinion/commentary: A recent large randomized controlled trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.     

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.     

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.     

A pharmacological overview of lamotrigine for the treatment of epilepsy

Introduction: Epilepsy is one of the most common neurological disorders, affecting about 2% of the population worldwide. Lamotrigine (LTG) is a second generation anti-epileptic drug (AED) with broad spectrum of activity, a favourable side-effect profile, simpler dosing than earlier drugs and efficacious in diverse epilepsy syndromes.

Areas covered: The present review focuses on pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability of LTG and its effect on cognition, psychiatry, quality of life, women and pregnancy along with effect of enzyme inducing and enzyme inhibiting drugs over LTG and their effect on serum level fluctuations by collecting data from various studies over the years until 2016.

Expert commentary: Results from various studies and clinical trials indicate that LTG possessed a favourable profile of anticonvulsant activity and good tolerability as a monotherapy/or add-on therapy in children and adult patients against several types of seizures and syndromes. It has wide clinical dose range with favourable pharmacokinetic properties making it an excellent therapeutic option in epilepsy.