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.     

Levetiracetam: a review of its use in epilepsy

Levetiracetam (Keppra?, E Keppra?) is an established second-generation antiepileptic drug (AED). Worldwide, levetiracetam is most commonly approved as adjunctive treatment of partial onset seizures with or without secondary generalization; other approved indications include monotherapy treatment of partial onset seizures with or without secondary generalization, and adjunctive treatment of myoclonic seizures associated with juvenile myoclonic epilepsy and primary generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsy. Levetiracetam has a novel structure and unique mechanisms of action. Unlike other AEDs, the mechanisms of action of levetiracetam appear to involve neuronal binding to synaptic vesicle protein 2A, inhibiting calcium release from intraneuronal stores, opposing the activity of negative modulators of GABA- and glycin-gated currents and inhibiting excessive synchronized activity between neurons. In addition, levetiracetam inhibits N-type calcium channels. Levetiracetam is associated with rapid and complete absorption, high oral bioavailability, minimal metabolism that consists of hydrolysis of the acetamide group, and primarily renal elimination. It lacks cytochrome P450 isoenzyme-inducing potential and is not associated with clinically significant pharmacokinetic interactions with other drugs, including other AEDs. The efficacy of oral immediate-release levetiracetam in controlling seizures has been established in numerous randomized, double-blind, controlled, multicentre trials in patients with epilepsy. Adjunctive levetiracetam reduced the frequency of seizures in paediatric and adult patients with refractory partial onset seizures to a significantly greater extent than placebo. Monotherapy with levetiracetam was noninferior to that with carbamazepine controlled release in controlling seizures in patients with newly diagnosed partial onset seizures. Levetiracetam also provided seizure control relative to placebo as adjunctive therapy in patients with idiopathic generalized epilepsy with myoclonic seizures or GTC seizures. In addition, patients receiving oral levetiracetam showed improvements in measures of health-related quality of life relative to those receiving placebo. Although treatment-emergent adverse events were commonly reported in the clinical trials of levetiracetam, the overall proportion of patients who experienced at least one treatment-emergent adverse event was broadly similar in the levetiracetam and placebo treatment groups, with most events being mild to moderate in severity. Levetiracetam is not associated with cognitive impairment or drug-induced weight gain, but has been associated with behavioural adverse effects in some patients.     

Spotlight on levetiracetam in epilepsy

Levetiracetam (Keppra?, E Keppra?) is an established second-generation antiepileptic drug (AED). Worldwide, levetiracetam is most commonly approved as adjunctive treatment of partial-onset seizures with or without secondary generalization; other approved indications include monotherapy treatment of partial-onset seizures with or without secondary generalization, and adjunctive treatment of myoclonic seizures associated with juvenile myoclonic epilepsy and primary generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsy. Levetiracetam has a novel structure and unique mechanisms of action. Unlike other AEDs, the mechanisms of action of levetiracetam appear to involve neuronal binding to synaptic vesicle protein 2A, inhibiting calcium release from intraneuronal stores, opposing the activity of negative modulators of GABA- and glycin-gated currents and inhibiting excessive synchronized activity between neurons. In addition, levetiracetam inhibits N-type calcium channels. Levetiracetam is associated with rapid and complete absorption, high oral bioavailability, minimal metabolism that consists of hydrolysis of the acetamide group and primarily renal elimination. It lacks cytochrome P450 isoenzyme-inducing potential and is not associated with clinically significant pharmacokinetic interactions with other drugs, including other AEDs. The efficacy of oral immediate-release levetiracetam in controlling seizures has been established in numerous randomized, double-blind, controlled, multicentre trials in patients with epilepsy. Adjunctive levetiracetam reduced the frequency of seizures in paediatric and adult patients with refractory partial-onset seizures to a significantly greater extent than placebo. Monotherapy with levetiracetam was noninferior to that with carbamazepine controlled release in controlling seizures in patients with newly diagnosed partial-onset seizures. Levetiracetam also provided seizure control relative to placebo as adjunctive therapy in patients with idiopathic generalized epilepsy with myoclonic seizures or GTC seizures. In addition, patients receiving oral levetiracetam showed improvements in measures of health-related quality of life relative to those receiving placebo. Although treatment-emergent adverse events were commonly reported in the clinical trials of levetiracetam, the overall proportion of patients who experienced at least one treatment-emergent adverse event was broadly similar in the levetiracetam and placebo treatment groups, with most events being mild to moderate in severity. Levetiracetam is not associated with cognitive impairment or drug-induced weight gain, but has been associated with behavioural adverse effects in some patients.     

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug-drug interactions have been explored across large adult and pediatric populations. The exposure-response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.     

GABA(A) receptor epilepsy mutations

Idiopathic generalized epilepsy (IGE) syndromes are diseases that are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities. Although it was long hypothesized that IGE had a genetic basis, only recently have causative genes been identified. Here we review mutations in the GABA(A) receptor alpha1, gamma2, and delta subunits that have been associated with different IGE syndromes. These mutations affect GABA(A) receptor gating, expression, and/or trafficking of the receptor to the cell surface, all pathophysiological mechanisms that result in neuronal disinhibition and thus predispose affected patients to seizures.     

Spotlight on topiramate in epilepsy

Topiramate (Topamax) is a structurally novel broad-spectrum antiepileptic drug (AED) with established efficacy as monotherapy or adjunctive therapy in the treatment of adult and paediatric patients with generalized tonic-clonic seizures, partial seizures with or without generalized seizures, and seizures associated with Lennox-Gastaut syndrome. The incidence and severity of many adverse events, including CNS-related events, may be reduced through the use of slow titration to effective and well tolerated dosages. It is associated with few clinically significant interactions with other drugs, is effective when used with other AEDs, is not associated with drug-induced weight gain and, at lower dosages, does not interfere with the effectiveness of oral contraceptives. Therefore, topiramate is a valuable option as monotherapy or adjunctive therapy in the treatment of epilepsy in adult and paediatric patients.     

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.     

Myoclonus precipitated by oral suspension of oxcarbazepine in idiopathic generalized epilepsy

Oxcarbazepine (OXC) is widely registered for the treatment of partial seizures and generalized tonic-clonic seizures (GTCS). Myoclonic seizures induced by OXC are uncommon. We report a child with idiopathic generalized epilepsy who developed myoclonic seizures and had an abnormal electroencephalogram (EEG) when oral suspension of OXC was introduced. This study suggests that oral suspension of OXC can precipitate myoclonus.     

Zonisamide: review of its use in epilepsy therapy

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.     

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.     

Oxcarbazepine: an update of its efficacy in the management of epilepsy

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a 10-keto analogue of carbamazepine with anticonvulsant activity. In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective as phenytoin and vaiproic acid at reducing generalised tonic-clonic and partial seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. The most commonly reported adverse events associated with oxcarbazepine monotherapy and/or adjunctive therapy in adults and/or children are somnolence, dizziness, headache, nausea and vomiting. Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults and children) and valproic acid (in adults), and although 75 to 90% of adult patients in 5 recent monotherapy studies reported adverse events while receiving oxcarbazepine, <8% withdrew from treatment because of them. Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of patients treated with oxcarbazepine. Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. Although oxcarbazepine does have a clinically significant interaction with some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for interactions than older antiepileptic drugs (AEDs) because its major metabolic pathway is mediated by noninducible enzymes. CONCLUSION: Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults and children. Furthermore, it is also effective as adjunctive therapy in the treatment of refractory partial seizures in both age groups. In addition, the drug is tolerated better than the older, established AEDs, and has a lower potential for drug interactions. These attributes make oxcarbazepine an effective component in the initial treatment of newly diagnosed partial and generalised tonic-clonic seizures, and also as an adjunct for medically intractable partial seizures in both adults and children.     

Pharmacotherapy of epilepsy: newly approved and developmental agents

This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development. Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200-600 mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related. Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200?mg/day. Adverse effects include dizziness and somnolence. Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200 mg/day, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness. Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported. Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete. Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABA(A) receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients. The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy.     

Topiramate: a review of its use in the treatment of epilepsy

Topiramate (Topamax) is a structurally novel broad-spectrum antiepileptic drug (AED) with established efficacy as monotherapy or adjunctive therapy in the treatment of adult and paediatric patients with generalised tonic-clonic seizures, partial seizures with or without generalised seizures, and seizures associated with Lennox-Gastaut syndrome. The incidence and severity of many adverse events, including CNS-related events, may be reduced through the use of slow titration to effective and well tolerated dosages. It is associated with few clinically significant interactions with other drugs, is effective when used with other AEDs, is not associated with drug-induced weight gain and, at lower dosages, does not interfere with the effectiveness of oral contraceptives. Therefore, topiramate is a valuable option as monotherapy or adjunctive therapy in the treatment of epilepsy in adult and paediatric patients.     

Genetic animal models of epilepsy as a unique resource for the evaluation of anticonvulsant drugs. A review

Genetic animal models of epilepsy comprise genetically predisposed animal species in which seizures either occur spontaneously or in response to sensory stimulation. The major advantage of these naturally occurring epilepsies in animals as models of human epilepsy is that they simulate the clinical situation more closely than any other experimental epilepsy. Models with idiopathic spontaneous recurrent seizures are epileptic dogs, tottering mice, and rats with spike-wave absence (petit mal) seizures. In dogs, the most common seizure type are generalized tonic-clonic (grand mal) seizures. Recent epidemiological and antiepileptic drug efficacy studies strongly suggest that epileptic dogs offer a valuable model for human grand mal epilepsy. In tottering mice, two types of spontaneous recurrent seizures occur: spike-wave absence seizures and focal motor seizures. Both types differ in sensitivity to common antiepileptic drugs, which closely resembles the absence and focal types of epilepsy in humans. Spontaneously recurrent spike-wave absence seizures in rats can be selectively blocked by drugs effective in petit mal (absence) epilepsy in man, demonstrating the validity of this new petit mal model for anticonvulsant drug screening. Models with reflex seizures comprise photosensitive baboons (Papio papio) and fowl, audiogenic seizure susceptible mice and rats, and gerbils with seizures in response to different sensory stimuli. With respect to seizure types and drug efficacies in these species, rats and chickens may represent suitable models for grand mal epilepsy, whereas baboons offer a useful model of photomyoclonic seizures. Gerbils can be subdivided into animals with minor (myoclonic) and major (mostly generalized tonic-clonic) seizures, which respond differently to antiepileptic drugs and seem to provide interesting models for petit mal and grand mal epilepsy in man. In conclusion, the data summarized in this review emphasize that genetic animal models of epilepsy offer unique approaches to the evaluation of antiepileptic drugs used or usable in man.     

Topiramate: a review of its use in childhood epilepsy

Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels). In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related. Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day. Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a > or =50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a > or =50% reduction in seizures was maintained in 7 of 11 children. Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing studies. CONCLUSION: Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjuntive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children.     

Oxcarbazepine: a review of its use in children with epilepsy

Oxcarbazepine (Trileptal, Timox) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels. In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalized tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43-71% of patients with partial onset, generalized or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7-50 mg/kg/day; duration 1-5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited). As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalization: the median percentage change in partial onset seizure frequency was 35% vs 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5-56.7 mg/kg/day), 7-11% of patients with partial onset or generalized seizures were seizure free during treatment, and 20-54% had seizure reductions of > or=50%. Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient. Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used. In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.     

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.     

Ion channel defects in idiopathic epilepsies

Idiopathic epilepsies are genetically determined diseases of the central nervous system characterized by typical epileptic seizures and EEG abnormalities but not associated with structural brain lesions. In recent years, an increasing number of mutations associated with idiopathic epilepsy syndromes were identified in genes encoding subunits of voltage- or ligand-gated ion channels. These encouraging results provide a plausible pathophysiological concept, since ion channels form the basis for neuronal excitability and are the major targets for anticonvulsive pharmacotherapy. The first epilepsy genes were identified for rare autosomal dominant syndromes within large pedigrees. Recently, a few mutations were also found for the frequent classical forms of idiopathic generalized epilepsies (IGE), for example absence or juvenile myoclonic epilepsy. The mutations can affect ion channels which on one hand have been known since several decades to be crucial for neuronal function, such as the voltage-gated sodium channel or the GABA(A) receptor, or on the other hand were newly identified within the last decade as KCNQ potassium channels or the ClC-2 chloride channel. Functional studies characterizing the molecular defects of the mutant channels point to a central role of GABAergic synaptic inhibition in the pathophysiology of IGE. Furthermore, newly discovered genes may be suitable as novel targets for pharmacotherapy such as KCNQ channels for the anticonvulsant drug retigabine. Altogether, these genetic and pathophysiological investigations will enhance our knowledge about the understanding of epileptogenesis and can help to improve anticonvulsive therapy.     

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.     

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.