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Brain & Development 30 (2008) 549­555 www.elsevier.com/locate/braindev

Review article

New antiepileptic drugs in pediatric epilepsy

Hee Hwang, Ki Joong Kim *

Department of Pediatrics, Seoul National University Childern's Hospital, 28 Yongon-dong, Jongno-gu, Seoul 110-744, South Korea Received 17 September 2007; received in revised form 21 January 2008; accepted 21 January 2008

Abstract New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy. Ó 2008 Elsevier B.V. All rights reserved.

Keywords: Antiepileptic drug; Pediatric epilepsy; Evidence-based

1. Introduction During the last decade, the two mainstays of epilepsy treatment, epilepsy surgery and antiepileptic drug (AED) therapy, have made great advances, resulting predominantly from advances in imaging techniques and the development of new AEDs. Nine new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide), introduced into the market since 1993, have given physicians new options for the treatment of patients with epilepsy. However, 25­30% of children with epilepsy are still refractory to these wider treatment options. Therefore, there remains a need to develop a drug that controls all epilepsies [1­3]. For ethical reasons, the new AEDs were approved as ``add-on therapies" based only upon clinical trials

Corresponding author. Tel.: +82 2 2072 3367; fax: +82 2 2072 3455. E-mail address: [email protected] (K.J. Kim). 0387-7604/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.01.007

*

involving adult patients [4]. These narrow and arbitrary criteria cause several problems in the application of the new AEDs. First, they only give a rough idea of the efficacy of the drugs, because the results were derived from combination therapies with conventional drugs. Second, some unexpected adverse reactions have been reported after licensing, such as with felbamate and vigabatrin [5]. Third, a few considerations relevant to pediatric patients were overlooked: age-specific organ toxicity, the impact on behavior and cognition, and the pharmacokinetic properties in the pediatric population [6,7]. Lastly, because of the lack of evidence-based data on the efficacy, safety, and mode of use of the new AEDs, their applications depend on the clinicians' own experiences. Recently, several publications have suggested evidence-based guidelines for the efficacy and tolerability of the new AEDs and offered expert opinions, including those concerned with pediatric patients, to facilitate more reasonable selection of the new AEDs [8­11]. In this article, we review the mechanisms of action, efficacy, pharmacokinetic properties, and adverse reac-

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tions of the new AEDs, focusing on pediatric patients. Tiagabine is excluded because it is not available in Korea. We also discuss the principles of AED selection for children, and future directions for AED development for pediatric patients. 2. Felbamate Felbamate (FBM) was introduced in 1993, and is characterized by several unique features during the development and release: FBM was the first AED to be tested in a double-blind fashion in refractory patients withdrawn from presurgical evaluations, was the first AED to be tested in double-blind monotherapy trials, and was the first drug to be tested in a placebo-controlled trial in children with Lennox­Gastaut syndrome [12]. Its exact mechanism of action is unclear. However, a few possible mechanisms have been suggested: the inhibition of N-methyl-D-aspartate (NMDA)-receptorrelated sodium currents, the potentiation of c-aminobutyric acid (GABA)-ergic activity, and the inhibition of voltage-gated sodium channels [13,14]. Initially, FBM was approved by the US Food and Drug Administration (FDA) for monotherapy or adjunctive therapy in adult patients with refractory partial seizures, and for adjunctive therapy for children with LGS (Class I evidence) [15]. Class III evidence exists for the use of FBM in pediatric epilepsies as an add-on treatment for infantile spasms, partial seizures, absence seizures, juvenile myoclonic epilepsy (JME), and Landau­ Kleffner syndrome (LKS) [16,17]. Despite its favorable efficacy, its primary indication in children is currently restricted to the adjunctive treatment of LGS because of its fatal toxicity. Expert opinion in the USA also suggests that FBM should be considered merely as an equivocal or second-line agent for LGS, and an inappropriate agent for all other types of seizures [11]. The initial recommended dose is 15 mg/kg/day divided into three or four doses, and can be titrated up to 45 mg/kg/day. In children, a higher dose of up to 90 mg/kg/day may be required for complete seizure control [18]. FBM can increase the serum levels of other AEDs, such as phenytoin, phenobarbital, valproic acid (VPA), and carbamazepine-10,11-epoxide by up to 20­50% [19]. The common adverse effects are anorexia, weight loss, insomnia, and gait disturbance, which are reversible after discontinuation or dose reduction [12]. FBM is also related to more serious, fatal toxicities: aplastic anemia and hepatotoxicity. The risk of aplastic anemia in FBM-prescribed patients is estimated to be 1:5000, and half of these cases are fatal [12,20]. No FBM-associated aplastic anemia has been reported in children younger than 13 years [21]. The prevalence of fatal hepatotoxicity, another serious FBM-related toxicity, is estimated to range from 1:7000 to 1:22,000, and its age preference is controversial [3,12,18,21].

3. Gabapentin Gabapentin (GBP), a nonpolar GABA analogue, was released in 1994. Although it has a similar structure to that of GABA, it does not bind GABA receptors and its mechanism of action appears unrelated to any direct effect on the GABA system [22]. It is speculated that GBP inhibits glutamate synthesis, potentiates GABA release, or inhibits GABA transaminase [14,18]. GBP has a few distinct pharmacokinetic properties that confer practical advantages: its minimal binding to proteins, a lack of any significant pharmacokinetic interactions, its elimination via the kidney, and the absence of hepatic oxidation induction. GBP has a relatively short elimination half-time (t1/2), so it is preferably divided into three or four doses [3,4,18]. The FDA has approved GBP as an adjunctive therapy for partial seizures in adults and children older than 12 years. There is evidence that GBP is effective as a monotherapy for newly diagnosed partial epilepsy. In contrast, there is no evidence that GBP is effective against primary generalized seizures [3,23]. One study reported Class I evidence of its efficacy and tolerability in newly diagnosed partial epilepsy, and four studies have reported Class I evidence of its efficacy in refractory partial epilepsy [8,9]. In the more recent and strict International League Against Epilepsy (ILAE) treatment guidelines [10], there are no data on its efficacy in children with partial-onset seizures; one Class III double bind (DB) trial showed its lack of efficacy in children with absence seizures and one Class III DB trial demonstrated its efficacy in children with benign rolandic epilepsy. Expert opinion in the USA [11] indicated that GBP can merely be considered a second-line agent for benign rolandic epilepsy, and there is a lack of consensus regarding its use for other partial-onset seizures. The recommended doses for pediatric patients range from 30 mg/kg/day to more than 90 mg/kg/day [2]. It is advised that the starting dose be reduced to 10 mg/ kg/day because of the possibility of its pharmacodynamic interaction with other AEDs. GBP is absorbed from the gut through a saturable transport mechanism so that higher doses may not correlate with proportionally higher serum levels [24]. The adverse effects of GBP are not serious. Behavioral changes, such as aggression or hyperactivity, are commonly noted, and weight gain, somnolence, dizziness, fatigue, ataxia, and other movement disorders (choreoathetosis) can be manifested [3,4,18,25]. 4. Lamotrigine Lamotrigine (LTG) is one of the broad-spectrum AEDs, and was initially indicated as a monotherapy and adjunctive therapy for partial and generalized sei-

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zures in adults. Its major mechanism of action is assumed to be in prolonging the slow inactivation of voltage-gated sodium channels, facilitating the inhibition of glutamate release [14]. It is metabolized predominantly by the liver, and this metabolism is accelerated by enzyme inducers, such as carbamazepine (CBZ) or phenytoin (PHT). Conversely, it is inhibited by enzyme inhibitors, such as VPA. These drug metabolism properties can explain the marked differences in LTG serum levels with the same LTG dose [3]. LTG is indicated as an adjunctive therapy for generalized seizures in children with LGS [26]. It also has a broad range of efficacy for diverse types of seizures: JME [27], infantile spasms [28], absence seizures [29], and Rett syndrome [30]. The paradoxical aggravation of myoclonic seizures by LTG should be kept in mind, especially in JME [31]. LTG is equivalent to VPA for patients with newly diagnosed childhood absence epilepsy, although LTG requires a much slower titration period [32]. One study reported Class II evidence of the efficacy of LTG under DB, placebo-controlled conditions in children with newly diagnosed absence seizures [8], and suggested that LTG can be included in the treatment options for these children. For children with refractory partial epilepsy, there has been no monotherapy trial, but one study has reported with Class I evidence of the efficacy of LTG as an adjunctive therapy [9]. LTG was shown to be efficacious for children with LGS, with Class I evidence, in one study and with Class II evidence in another [9]. The ILAE treatment guidelines [10] also indicate its broad spectrum of efficacy for various seizure types: one study reported Class III open-label (OL) evidence for children with partial-onset seizures; one study reported Class III DB evidence; one reported Class III OL evidence for children with absence seizures; and a few studies have reported Class IV evidence for children with JME. However, there is no adequate data for children with generalized-onset tonic­clonic seizures. One study reported Class IV evidence of the possible exacerbation of JME by LTG. In contrast, expert opinion in the USA [11] has made consensus on the efficacy of LTG. It can be applied as a first-line agent for older children with myoclonic and generalized tonic­clonic seizures. For children with cryptogenic complex partial seizures, LTG is considered as a second monotherapy after an initial trial of CBZ or oxcarbazepine. It is also appropriately used for children with LGS, next to VPA or topiramate. LTG can be the treatment of choice for children with absence seizures, except as an initial monotherapy in younger children or for children with JME, especially females. LTG is usually initiated at 0.5­2 mg/kg/day, but at 0.1­0.2 mg/kg/day in combination with VPA because

of the higher risk of a serious skin rash [3,4,31]. Slow titration is advisable, increasing the dose by 1 mg/kg/ day every 1 or 2 weeks without VPA and by 0.2­ 0.3 mg/kg/day every 1 or 2 weeks with VPA. The maintenance dose range is 5­15 mg/kg/day without VPA and 1­5 mg/kg/day with VPA. VPA increases the half-life of LTG from 24 to 60 h [24]. Common dose-related adverse effects are dizziness, sedation, headache, diplopia, and ataxia [3,4]. The most serious adverse effect is a skin rash, which can potentially evolve into lethal Stevens­Johnson syndrome. It is more common in pediatric patients, and occurs in up to 10% of patients, usually within the first 2­8 weeks after initiation [4]. Young age, rapid titration, and use in combination with VPA are known risk factors for skin rashes. 5. Levetiracetam Levetiracetam (LEV), a pyrrolidine derivative and an analogue of piracetam, was initially developed as a neurocognitive agent for Alzheimer's disease, and has a unique mechanism of action compared with those of other AEDs. It does not bind to benzodiazepine, GABA, or glutaminergic receptors, and does not affect sodium channels [18,33]. Its mechanism of action is unclear, but it possibly acts via a specific binding site within the brain. It causes a reduction in high-voltage-activated calcium currents, resulting in the modulation of intracellular calcium transients [3,4]. In an animal study, LEV inhibited kindling in mice [34]. Two thirds of the LEV dose is excreted in the urine, and the remaining one third is metabolized by hydrolysis [35]. LEV was initially approved as an add-on therapy for partial seizures in adults, but is currently also indicated for the treatment of myoclonic seizures in JME [3,5,18]. For the pediatric population, there does not exist Class I evidence for its use, and only Class III evidence is available from an OL trial of LEV as an adjunctive therapy for children with refractory partial epilepsy [36]. However, there is growing evidence of its broad-spectrum action and its efficacy in all seizure types of idiopathic generalized epilepsies (IGE) [37]. There is a lack of clinical data on its application in children with new-onset epilepsy, refractory IGE, or LGS [8,9]. According to the ILAE treatment guidelines [10], LEV can be indicated only for the treatment of JME, with Class IV evidence, and there is no evidence of its use for other pediatric epilepsies. Expert opinion in the USA [11] suggests a similar application of LEV for pediatric epilepsy. LEV is considered a second-line agent for myoclonic/generalized tonic­clonic seizures or LGS, and can usually be used appropriately for children with cryptogenic complex partial seizures.

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The usual pediatric dose of LEV is 15­30 mg/kg/day [38]. However, because its clearance is faster in children than in adults, higher doses may be required to achieve desirable serum levels. LEV is well tolerated [3,18,36], and its adverse effects are benign: somnolence, asthenia, headache, anorexia, and noninvasive infections [36,39]. The occurrence of leukopenia in the pediatric population, which develops in 3% of patients, is controversial. The major adverse effect leading to a discontinuation of LEV is behavioral changes, including hostility, emotional lability, depersonalization, and psychotic behavior, which are observed in 2% of patients [18,36]. 6. Oxcarbazepine Oxcarbazepine (OXC), a homologue of carbamazepine, is a prodrug, and its 10-monohydroxy metabolite exerts an anticonvulsant effect by blocking sodium channels. Although it has similarities to CBZ in its structure, efficacy, and adverse effect profiles, it has a pharmacokinetic difference in that there is no enzymatic autoinduction in OXC [3,4]. Children younger than 8 years have clearance rates 30­40% higher than those in older children [40]. Furthermore, unlike CBZ, OXC is not metabolized into the epoxide derivative [35]. OXC is predominantly indicated for the treatment of partial seizures, with a minor indication for the treatment of generalized tonic­clonic seizures [10,41,42]. Of course, like CBZ, it possibly precipitates or aggravates myoclonic seizures in IGE. Three studies with Class I evidence and one with Class II evidence have compared the efficacy and safety of OXC with those of old AEDs for both child and adult patients with newly diagnosed partial seizures or IGE [8,41,42]. These studies suggested that OXC is equivalent to CBZ and PHT in its efficacy, but is more tolerable, and that OXC is equivalent to VPA in its efficacy and tolerability. One study used Class I evidence to evaluate the efficacy of OXC as an adjunctive therapy for children with refractory partial epilepsy [9]. The ILAE treatment guidelines [10] report that OXC was established as an initial monotherapy for children with newly diagnosed partial-onset seizures, with Class I evidence. They also suggest that OXC has an efficacy similar to that of PHT in the treatment of children with generalized-onset tonic­clonic seizures, based on Class III DB evidence, and that OXC may simultaneously precipitate generalized-onset tonic­clonic seizures, based on Class IV evidence. Expert opinion in the USA [11] suggests similar options for its use. OXC should be considered a treatment of choice as an initial monotherapy for the treatment of cryptogenic complex partial seizures and benign rolandic epilepsy. It can be considered a second-line agent in symptomatic generalized tonic­clonic seizures. Initial dosing in pediatric patients usually begins at 10 mg/kg/day, and gradually increases up to 30 mg/kg/

day [35,40]. CBZ, PHT, PB, and VPA can be associated with decreased serum levels of the active metabolite. However, OXC may increase the serum levels of PB and PHT [35]. Dizziness, diplopia, nausea, and ataxia are well-known adverse effects of OXC, but show more benign profiles in children [18]. A serious skin rash can occur, which may evolve into Steven­Johnson syndrome or toxic epidermal necrolysis, but less frequently than with CBZ [43]. About 25­33% of patients with a hypersensitivity reaction to CBZ also have an allergic reaction to OXC, the so-called ``cross-hypersensitivity reaction" [3,44]. Hyponatremia is another well-known adverse effect of OXC, and its incidence is estimated to be 0.4­ 1%. Sodium concentrations return to normal with dose reduction, discontinuation of the drug, or fluid restriction [44]. 7. Topiramate Topiramate (TPM), a fructopyranose compound, has a broad spectrum of efficacy. At least three different mechanisms of action have been suggested: the inhibition of voltage-gated sodium channels, the inhibition of glutaminergic a-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid-receptor-mediated sodium currents, and the potentiation of GABA-receptormediated chloride currents [14]. Its activity as a weak carbonic anhydrase inhibitor may not contribute significantly to its efficacy [3]. The clearance rates of TPM are inversely dependent on the age of the patient, so that younger patients have higher clearance rates and the drug a shorter half-life. The clearance rate in children is approximately 50% greater than that in adults. Therefore, the serum concentration is 33% lower in children at the same dose [45]. Current indications for TPM, with Class I evidence, are as an adjunctive therapy for adults and children of 2­12 years of age with partial seizures or primary generalized tonic­clonic seizures [3,18]. However, some published data suggest its use in various pediatric epilepsies: LGS, infantile spasms, JME, and refractory partial seizures [45­48]. There are two Class I studies of the use of TPM for the treatment of patients with newly diagnosed partial or generalized epilepsy, including both children and adults [8]. These studies suggest that TPM is equivalent in efficacy and safety to CBZ in controlling partial seizures and to VPA in treating idiopathic generalized seizures. One study, with Class I evidence, estimated the efficacy of TPM as an adjunctive therapy in children with refractory partial seizures; one with Class I evidence and one with Class IV evidence assessed the efficacy of TPM as an adjunctive therapy in children with LGS [9]. The ILAE treatment guidelines [10] cite three clinical trials of TPM, with Class III DB evidence, in children with partial-onset seizures, and two Class III DB trials in children with generalized-

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onset tonic­clonic seizures, which indicated that TPM has a similar efficacy/effectiveness as CBZ and VPA, with a dose-dependent response. Class IV studies have suggested that TPM has some efficacy in patients with newly diagnosed JME. Expert opinion in the USA [11] describes more detailed indications for TPM in various seizure types. TPM can be a first-line agent in myoclonic and generalized tonic­clonic seizures next to VPA, and may be considered the first monotherapy in symptomatic generalized tonic­clonic seizures in healthy infants. TPM cannot be a first-line agent in an initial monotherapy for cryptogenic complex partial seizures, but may be considered as a first-line agent in the second monotherapy after CBZ, PHT, or OXC. For LGS, TPM is considered as a first-line agent in the initial monotherapy next to VPA, but is considered the treatment of choice as the second monotherapy after VPA or LTG. It may also be used as a second-line agent for infantile spasms caused by tuberous sclerosis, and as a first-line agent for other symptomatic infantile spasms. Lastly, it can be considered as a first-line agent in JME next to VPA and LTG. TPM is usually initiated at 1.0 mg/kg/day, and maintained in a range of 3­8 mg/kg/day [45]. The common adverse effects include somnolence, hypo- or anhydrosis, paresthesia, nystagmus, problems with concentration and word finding, decreased appetite, and weight loss [4,45]. TPM frequently induces or facilitates metabolic acidosis, especially in patients with renal disease or those on a ketogenic diet or zonisamide [49]. Nephrolithiasis can occur in 1.5% of patients, possibly caused by its carbonyl anhydrase inhibitor activity [18]. 8. Vigabatrin Vigabatrin (VGB), a synthetic derivative of GABA, is an irreversible GABA-aminotransferase inhibitor [50]. It binds irreversibly to GABA transaminase, resulting in a decrease in the synaptic breakdown of GABA [3]. In children, VGB is useful in the treatment of partial-onset seizures and LGS. On the contrary, it may aggravate myoclonic seizures [51,52]. It has emerged as a first-choice AED in the treatment of infantile spasms, particularly those accompanied by tuberous sclerosis [53]. However, VGB is currently unavailable on the US market because of its irreversible adverse effect, visual-field constriction. Even in other countries where VGB is marketed, its use for patients with epilepsy is restricted, and it is given with appropriate caution. Therefore, the practice parameters recommended by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) [8,9] do not contain any information on VGB. In contrast, the ILAE treatment guidelines [10] cite one clinical trial of VGB, with Class III OL evidence, for the treatment of children with partial-onset seizures. This trial sug-

gests that VGB is potentially efficacious or effective as an initial monotherapy for untreated pediatric partial-onset seizures. According to expert opinion in the USA [11], VGB is the treatment of choice for infantile spasms secondary to tuberous sclerosis, and may also be a second-line agent for the treatment of other symptomatic infantile spasms. Pediatric doses range from 50 mg/kg/day to 150 mg/ kg/day [4]. Its pharmacokinetic properties are similar to those of GBP: nonhepatic metabolism, and a lack of pharmacokinetic interactions. Fatigue, headache, dizziness, ataxia, tremor, weight gain, and hyperactivity are commonly noted. Irreversible visual-field constriction is the main concern. Periodic ophthalmological examinations every 3 months should be recommended for patients treated with VGB [54,55]. 9. Zonisamide Zonisamide (ZNS) is a sulfonamide derivative. It may facilitate dopaminergic and serotoninergic neurotransmission through the blockade of T-type calcium channels and the prolongation of sodium channel inactivation [56,57]. It is also a weak inhibitor of carbonic anhydrase. It has a relatively long half-life (60­ 80 h), and is metabolized by the liver. It was first developed in Japan, and large-scale OL clinical trials were performed before its approval in other countries. The results suggested that it had a broad spectrum of efficacy for pediatric partial and generalized-onset seizures, especially for myoclonic epilepsies [58,59]. Globally, it is indicated for the treatment of partial seizures, and further reports have demonstrated its efficacy in LGS, primarily in generalized tonic­clonic seizures [3,18]. There has been no clinical trial of ZNS for the treatment of patients with newly diagnosed epilepsy in the practice parameters published by the AAN and AES [8,9]. They consider ZNS to be in the level U category (insufficient evidence) for pediatric refractory partial seizures. No clinical trial of ZNS is cited in the ILAE treatment guidelines [10], except for JME, with Class IV evidence. In contrast, expert opinion [11] suggests broader applications of ZNS. It may be a first-line agent for children with myoclonic and generalized tonic­clonic seizures next to VPA, and a second-line agent in second monotherapy for children with cryptogenic complex partial seizures. It can also be considered as a second-line agent for infantile spasms, LGS, and JME. The usual starting dose is 2­4 mg/kg/day, and the maintenance dose is 4­8 mg/kg/day [4,57]. Enzymeinducing AEDs can increase the elimination of ZNS because it is metabolized in the liver [58]. Somnolence, poor appetite, weight loss, headache, pruritus, and skin rash are commonly observed adverse effects [4,58]. Urolithiasis occurs in 1.9­3.5% of patients in Western series

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[4,18]. In Japanese series, the occurrence is much lower (0.2%) [58]. Oligohydrosis and hyperthermia are rarely reported [3,4,18,60]. 10. Conclusions The selection of an AED for pediatric epilepsy is not a simple task. Numerous variables should be considered [10], including AED-specific variables (seizure- or epilepsy-syndrome-specific efficacy/effectiveness, adverse effects, pharmacokinetics, formulations, and so on), patient-specific variables (genetic background, sex, age, comorbidities, socio-economic status), and nation-specific variables (AED availability, AED cost). The introduction of new AEDs is welcomed by both physicians and patients. However, it often creates a dilemma in deciding the best treatment option. Furthermore, in pediatric populations, special issues such as age-specific organ toxicity, the impact on behavior or cognition, and the pharmacokinetic properties in childhood must be considered. The naive selection of an AED without indi¨ vidualization or tailoring cannot guarantee a satisfactory treatment outcome. For this reason, the advantages of the new AEDs (equivalent efficacy and improved tolerability) [6] should be highlighted. Evidence-based guidelines are of value in that they encourage the physician to choose the most reasonable solution. However, physicians frequently encounter a gap between the available guidelines and clinical practice. Level A or B recommendations only endorse a proportion of the new AEDs. This may be attributable to the lack of well-designed, randomized controlled trials, and to the brief history of the new AEDs [6,10]. To overcome these limitations, neurologists should constantly contrive new study designs, such as high-dose versus low-dose comparisons, the adjustment of the time schedule, narrow targeting (age-specific or epileptic-syndrome-specific design), and so on [9,10]. Expert consensus offers many advantages to complement evidence-based guidelines. However, it must be used only as an expert basis for selecting the most reasonable AED for a specific patient, and not as a regulatory tool. The consensus opinion may be wrong, or can change with advances in the technology or in response to the accumulation of experience. Despite the introduction of new AEDs, 25­30% of children with epilepsy remain refractory to medical therapy. Therefore, the development of new AEDs should be continued, especially those targeting pediatric epilepsies and developing brains [6,7,61]. Adaptive designs that address the special concerns of children are required, supported by toxicology and formulation work [61]. Lastly, multicenter trials on a nationwide basis are essential to compensate for the small recruitment samples that result from the multiplicity of seizure types.

Acknowledgement This paper was read at Japanese Society of Child Neurology meeting on July 2007 as an invited lecture of Korea­Japan exchange program. References

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