Highlights of a satellite symposium held at the 10th European Paediatric Neurology Society Congress, 25–28 September 2013, Brussels, Belgium
Key points:
– Challenges of managing childhood epilepsy are heightened by the need to focus on the development of the child, as well as their epilepsy; in particular, by the potential effects of both seizures and AED treatment on the child’s neurodevelopment
– There is a need to increase the knowledge base to inform treatment decisions through well-designed clinical trials of AEDs and real-world data in the paediatric population
– Zonisamide is the latest AED to have gained a paediatric license for the adjunctive treatment of partial seizures, approval being based on a randomised controlled trial that followed stringent regulatory requirements
– Since many paediatric patients are refractory to treatment, there continues to be a need for further AEDs, particularly those with novel mechanisms of action
– Perampanel – a first-in-class, selective, non-competitive AMPA receptor antagonist – is the latest approved AED. This has been shown to be efficacious and generally well tolerated as adjunctive therapy in adolescent patients with refractory partial seizures
Management of childhood epilepsy is particularly challenging, since treatment decisions may not only affect a child’s current health status, but also their longer-term development. Key issues affecting the management of children with epilepsy were the focus of the Eisai-sponsored symposium at the recent 10th European Paediatric Neurology Society Congress in Belgium, which was entitled ‘Management of childhood epilepsy – are we on the right track?’ and chaired by Professor Lieven Lagae (University of Leuven, Belgium).
Professor Helen Cross (UCL Institute of Child Health and Great Ormond Street Hospital, London, UK) began by discussing the challenges associated with diagnosing epilepsy in children, highlighting the complexity of accurate diagnosis among the plethora of childhood syndromes. She stressed the importance of getting the patient’s diagnosis correct, since inappropriate treatment may exacerbate the child’s seizures. Professor Cross highlighted that children with epilepsy are at an increased risk of cognitive and behavioural problems, the reasons for which are complex and multifactorial. Seizure activity can itself have damaging effects on a child’s neurodevelopment, which may already be impaired by their underlying pathology. In addition, antiepileptic drugs (AEDs) may have adverse cognitive and behavioural side effects. Treatment decisions must therefore weigh the potential risks and benefits for each individual child – seizures are not the only consideration. Professor Cross also discussed the challenges involved in providing appropriate management and support to paediatric patients and their families throughout a child’s development, including the transition of care from paediatric to adult services.
Dr Stéphane Auvin (Inserm and Hôpital Robert Debré, Paris, France) then focussed on the need for clinical evidence to inform treatment decisions; in particular, the need for different types of evidence – from clinical trials and clinical practice – to provide an overall picture of the likely risks and benefits of a particular treatment approach. He began by highlighting that regulatory requirements for paediatric epilepsy have become increasingly stringent, an important aspect of this being the assessment of an AED’s long-term impact on cognition, growth and development. Despite the need for well-designed clinical trials, relatively few have been conducted in the paediatric population to date. The most recent of these was a Phase III trial assessing the safety and efficacy of adjunctive zonisamide for the treatment of partial seizures in children, results of which formed the basis for zonisamide gaining its paediatric license in this setting.1 In this trial, zonisamide was shown to be well tolerated and significantly more effective than placebo in reducing partial seizure frequency, the proportion of children experiencing ≥50% seizure frequency reduction over the 12-week maintenance period being 50% with zonisamide versus 31% with placebo (p=0.0044).1 Importantly, an extension study demonstrated that long-term treatment with zonisamide was associated with no consistent detrimental effects on long-term growth and development; overall, no new or unexpected safety signals emerged and the efficacy of zonisamide was maintained over a treatment period of at least 1 year.2,3 Dr Auvin went on to reiterate that, since clinical trials are conducted under tightly controlled conditions, there is a need for ‘real-world’ evidence from clinical practice to complement data from clinical trials, illustrating this with a case study of the use of zonisamide in his practice. Dr Auvin also highlighted that clinical trials are difficult to conduct in patients with rare conditions, a problem that has been addressed by the Orphan Drug Law, which lessened the statistical burden for proof of efficacy in Phase III trials, in recognition of low patient numbers. Conditions for which AEDs have been granted orphan drug status include Dravet syndrome and Lennox-Gastaut syndrome. Dr Auvin stressed that there is a particular need for long-term safety surveillance for drugs developed in this way, including the use of registries and evidence from clinical practice, underlining the importance of real-world data.
Professor Elena Belousova (Moscow Institute of Pediatrics and Pediatric Surgery, Russia) discussed the need for further treatment options, particularly those with novel mechanisms of action. She pointed out that, despite the availability of a wide range of AEDs, 20–40% of children fail to respond to their first AED therapy.4 However, other data have shown that almost one in five patients become seizure free with the addition of an alternative AED after failure of two to five agents,5 so it is still worth persisting with alternative treatment options in refractory patients. Professor Belousova went on to focus on the latest AED to have gained a license – perampanel – a first-in-class, selective, non-competitive AMPA receptor antagonist. Professor Belousova presented pooled data from three Phase III trials demonstrating that adjunctive perampanel treatment was generally well tolerated and provided improvements in seizure outcomes in adolescent patients (n=143; age 12–17 years) with refractory partial epilepsy over a treatment period of 19 weeks, as per the overall population.6,7 An extension study demonstrated that adjunctive perampanel continued to be generally well tolerated over a treatment period of up to 12 months, and that its efficacy was maintained throughout treatment, the proportion of patients demonstrating ≥50% seizure frequency reduction ranging from 40–60% during weeks 27–52.8 Professor Belousova supported these findings with a case study of her personal experience of using perampanel in clinical practice. She concluded by remarking that more recent AEDs are aiming to advance the concept of efficacy (antiepileptic potency) to efficiency (effectiveness plus tolerability), which may translate into improved quality of life for patients.
Despite the considerable difficulties associated with managing childhood epilepsy, an expanding evidence base and advances in drug development are helping to tackle some of these key challenges.
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