Eslicarbazepine acetate is a third-generation drug in the carboxamide family (CBZ, OXC) that acts by blocking voltage-gated sodium channels, resulting in a slow inactivation of neuron excitability. It was initially authorised for use in adults in Europe by the EMA in 2010 and later in 2013 in the United States by the FDA for adjuvant treatment of focal-onset seizures with or without secondary generalization. This indication was subsequently extended to include use as monotherapy. Since 2017 it has been authorised for use in the paediatric population for adjuvant treatment of focal-onset seizures with or without secondarily generalised seizures in children aged 4 or more years (FDA) or children aged 6 or more years (EMA), making it the first antiepileptic drug approved for use in children based on extrapolation. The main advantages of ESL are its administration as a single daily dose (which facilitates adherence to treatment), the absence of significant interactions with other drugs and a favourable safety profile, as no significant changes in haematology or chemistry parameters have been described. In this regard, hyponatraemia tends to be less frequent in comparison with OXC.11,16 The adverse effects seem to be dose-dependent and are presented in Table 2. This drug does not seem to cause cognitive or behavioural adverse effects in children.17

Lacosamide is a functionalised amino acid that acts on the neuron by enhancing selective slow inactivation of voltage-gated sodium channels. It does not affect rapid inactivation, so it is believed to modulate the pathological neuronal hyperexcitability without altering the physiological function of the cell.18 It was first authorised for use in adults aged more than 17 years by the FDA (2008) for adjuvant treatment of focal-onset seizures with or without secondary generalization. Since 2017, it has been authorised by the EMA and the FDA for use as monotherapy or add-on treatment in children from age 4 years. Lacosamide has the advantage of being an effective, safe and well-tolerated drug in the paediatric population, with little interaction with other drugs and that may delivered by both the enteral and parenteral routes. Furthermore, based on case series published in the past 5 years, in the future it could be considered a safe and effective treatment for status epilepticus and refractory status epilepticus in the paediatric age group.19Table 2 presents the most frequent adverse events, revealing a favourable neurotoxicity profile: depression in 9.5%, memory changes in 7.4% and other forms of cognitive impairment in 4.3%.11,20

Retigabine (international nonproprietary name) or ezogabine (United States adopted name) exhibits a unique mechanism of action among antiepileptic drugs, as it acts by activating KCNQ2-5 potassium channels, although it also modulates GABA receptors.4,10 This drug was authorised by the FDA and the EMA in 2011 for treatment of focal epilepsy with or without secondarily generalised seizures in adults. Later on, authorization was withdrawn by both agencies (FDA in 2017, EMA in 2018) upon request from manufacturer due to adverse effects involving skin pigmentation and the retina, so it is not currently available. It was never authorised for use in the paediatric population, and there is a single article in the paediatric literature describing successful treatment of a girl aged 8 years with ring chromosome 20 syndrome. The region where this fusion occurs most frequently is q13.3, where the KCNQ2 gene is located.21

Perampanel is one of the drugs authorised most recently for treatment of epilepsy in children (FDA 2018), although it has been authorised for treatment of adults and children aged 12 or more years since 2012. It acts as a highly selective non-competitive AMPA glutamate receptor antagonist (localized at excitatory synapses, post-synaptically), which makes its mechanism of action unique among the antiepileptic drugs. The inhibition results from the modulation of fast excitatory synaptic transmission.22,23 In adults and children aged more than 12 years, it is indicated for treatment of focal-onset seizures with or without secondary generalization (FDA and EMA, 2012) and of generalised tonic-clonic seizures (EMA and FDA, 2015). In 2018, the FDA expanded the indication to children aged 4 or more years with focal-onset seizures with or without secondary generalization based on extrapolated data after performance of safety and pharmacokinetic studies. Authorization in this age group by the EMA is still pending.13 Furthermore, several studies in children and adolescents have demonstrated its effectiveness in the treatment of focal-onset seizures.22 The main advantages of PER are the low incidence of cognitive side effects, its route of administration, the single daily dose that facilitates adherence to treatment and its favourable risk/benefit ratio. Adverse effects are more frequent in children aged more than 12 years compared to younger children, and they have been described in up to 70% of patients. Psychiatric changes are among the most significant adverse effects it causes (Table 2), including aggressiveness and irritability, which seem to be dose-dependent and have been described in 8.2% to 14% of treated children. They are most frequent in the first 6 weeks of treatment and in patients with psychiatric comorbidities, such as ADHD or personality disorders.10,22

Everolimus is a drug that in paediatric neurology is mainly used for management of diseases secondary to tuberous sclerosis complex (TSC), a neurocutaneous syndrome with a low prevalence (1 in 6000 births) that is, however, characterised by significant morbidity involving multiple systems and specifically the central nervous system. It is an inhibitor of complex 1 of mTOR (the mammalian target of rapamycin) indicated in patients with TSC for management of subependymal giant cell astrocytoma (SEGA), renal angiomyolipomas and epilepsy. Epilepsy is the most frequent disorder found in patients with TSC (85% of patients), usually with onset in the first year of life (2 out of 3 cases), manifesting either with focal-onset seizures or epileptic spasms. In more than 60% of patients, the seizures are drug-resistant.24 Evidence of its usefulness as an anticonvulsant first emerged during clinical trials of EVR for treatment of SEGA.25,26 Later on, based on the findings of the EXIST-3 trial (an international prospective multicentre double-blind randomised controlled study, n=366),27) the EMA (2017) and the FDA (2018) authorise the indication for use as an adjuvant antiepileptic drug in adults and children aged at least 2 years with drug-resistant focal-onset seizures associated with TSC. Treatment with EVR needs to be adjusted as needed while monitoring its plasma levels, and is likely to produce adverse events (Table 2), with stomatitis being the complication that most frequently leads to a dose reduction or discontinuation of the drug.11,27

Brivaracetam is a modified analogue of levetiracetam (LEV), so it has a similar mechanism of action through binding to synaptic vesicle protein 2A (SV2A), although BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV.10,28 Its also exhibits partial inhibition of voltage-gated sodium channels. Brivaracetam was first authorised for adjuvant treatment of focal-onset seizures in patients aged 16 or more years in 2016 (FDA, EMA), with its indications later expanding to use as monotherapy (2017) and finally to use in the paediatric population aged 4 or more years (2018) based on extrapolation.

The main advantages of BRV is that it is a safe and effective drug that can be administered enterally or parenterally and that it is very promising due to the high effectiveness it has exhibited against different types of seizures in animal models.13 Its adverse effects are infrequent and are presented in Table 2. We ought to mention that it seems to have fewer adverse behavioural effects compared to LEV.29 Its drawbacks is that it has exhibited more drug-drug interactions compared to LEV, as it can alter the function, and its function be altered by, other hepatic enzyme inducers.10

Cannabidiol is a molecule obtained from the cannabis plant, but unlike tetrahydrocannabinol (THC) it does not interact with cannabinoid receptor B1, so it has antiepileptic effects but no psychoactive effects.30 Its mechanism of action is not fully understood, but it is hypothesised that it may involve an increase in GABA activity through the modulation of the GABA-A receptor, which in turn could regulate intracellular calcium flux through various receptors (TRPV, VDAC, GPR55), and that it may have a mild anti-inflammatory effect mediated by adenosine.10,31 Recently, the FDA (2018) and the EMA (2019) have added the indication of management of seizures in patients aged 2 or more years with Dravet syndrome or Lennox-Gastaut syndrome. The efficacy of CBD was proven in 3 double-blind randomised controlled trials conducted in the paediatric and adult populations,30,32,33 although there is also evidence from other studies suggesting that it may be effective in other forms of epilepsy and epileptic syndromes.34,35 Its main advantage is that it has proven effective in 2 of the epileptic syndromes that are most difficult to control. Its main drawbacks are that it frequently produces adverse events (Table 2), that it interacts with several other antiepileptic drugs and that it may cause hepatotoxicity, especially when used in combination with VPA or VPA and CLB, which requires close monitoring of laboratory parameters (Table 3).

In this article, we attempted to summarise the main characteristics of the new AEDs used in paediatrics. Most of these third-generation drugs are effective, safe and generally well tolerated in children. If we focused on those intended for broader use (BRV, ESL, LCM, PER), while their effectiveness has been inferred by the extrapolation of data from studies in the adult population, it will be the day-to-day clinical experience that will reveal the true potential of these drugs, probably leading to expanding their spectrum and defining new indications or synergistic effects with other treatments (as has been the case of most antiepileptic drugs in the past). A recently published, large meta-analysis (it analysed 19 double-blind randomised controlled trials, with n=7245) on the use of third-generation anticonvulsants (ESL, LCM, PER, BRV) in adults with focal epilepsy did not find significant differences in effectiveness, although the data suggested that BRV was better tolerated compared to the other drugs, independently of the dose used.36 Thus, taking into account that all of these drugs seem to be equally effective and safe, the management of epilepsy is becoming increasingly individualised, with selection of one drug or another based on tolerance, synergistic effects, interactions or contraindications, although the goal of treatment remains the same for all: to improve the quality of life of children with epilepsy and their families.