while 85% of children experiencing a 50% reduction in total seizure frequency at least in the short term (Feucht and Brantner-Inthaler 1994). Other authors (Schmidt and Bourgeois 2000) consider VGB as a fourth-line treatment. At the present time, in most countries, the use of this drug is restricted to West syndrome because of the occurrence of visual ﬁeld defects. Newer antiepileptic drugs Felbamate (FBM) FBM, a carbamate-type anticonvulsant, showed a broad spectrum and several modes of action (White et al 2007) in preclinical trials (ability to limit the spread of seizure activity and to raise seizure threshold, to modulate the glycine NMDA receptor and to be a weak inhibitor at the BZD GABA-A receptor). This AED was the ﬁrst to be approved for adjunctive therapy in LGS after a double-blind, randomized, placebo-controlled study showed a signiﬁcant effect on “major” seizures (FBM study group 1993). Open studies (Dodson et al 1993; Jensen 1994; Gay et al 1995; Avanzini et al 1996; Eriksson et al 1998) and another double-blind study (Siegel et al 1999) conﬁrmed these initial results. Unfortunately, FBM is intensively metabolized and severe life-threatening adverse events (aplastic anemia and hepatic failure) appeared a few months after approval, limiting FBM use since 1994 to cases refractory to other AEDs. A review of the past 10 years of clinical experience (more than 35,000 new cases) has demonstrated that the risk/beneﬁt of FBM therapy supports its use as an important add-on option for patients with highly refractory epilepsies (Pellock et al 2006). However, in some countries, its use has been restricted to refractory LGS despite efﬁcacy in focal epilepsy. Lamotrigine (LTG) LTG, with its Na+ channel blocking actions, was initially introduced for add-on therapy of focal seizures in adults, but it was rapidly demonstrated that it was a broad spectrum AED. Additional mechanisms of action have been demonstrated, including stabilizing neural membranes and inhibiting the release of excitatory (glutamate and aspartate) neural transmitters (White et al 2007). Current data demonstrate efﬁcacy against focal seizures, tonic-clonic seizures, tonic seizures, absence seizures, and atonic seizures. More recently (Cianchetti et al 2002; Conry 2004), LTG was shown to be effective in West syndrome. From the early 1990s, apparent efﬁcacy in open-label studies (Timmings et al 1992; Schlumberger et al 1994; Donaldson et al 1997; Farrell et al 1997) in LGS led to double-blind, randomized clinical Neuropsychiatric Disease and Treatment 2008:4(6) Lennox-Gastaut treatment trials (Motte et al 1997; Eriksson et al 1998), conﬁrming a statistically signiﬁcant improvement, at least in major seizures. Worsening or no improvement of myoclonic jerks has been reported in LGS (Donaldson et al 1997; Dulac and Kaminska 1997) and related syndromes. Most children with LGS already receive one or more AED, and the addition of LTG can be difﬁcult if they are already being treated with an enzyme-inducing AED, VPA or both. Co-medication may have a dramatic effect on the half-life of LTG (and consequently on efﬁcacy and acute adverse events), and on safety issues, particularly the risk of rash, which is as high as 5% to 10% in younger patients. Titration of LTG thus requires careful attention, especially in children. Topiramate (TPM) Like LTG, TPM has several modes of action (modulation of voltage-dependent Na+ channels, potentiation of GABA-induced chloride ﬂuxes, and decreased glutamatergic excitability [blockade of kainate glutamate receptors]). TPM was initially approved for use in focal seizures in adults, and later also for children and in generalized tonic-clonic seizures. However, TPM also showed efﬁcacy in drop attacks associated with LGS in open (Uvebrandt and Bauzière 1994; Sachdeo et al 1996; Glauser et al 1997; Ritter et al 1998) and in double-blind studies of patients with refractory epilepsies, including LGS (Glauser et al 1998). In 1999, a double-blind randomized study (Sachdeo et al 1999) conﬁrmed the efﬁcacy of TPM in reducing the frequency of atonic seizures associated with LGS. Additional studies and small series have conﬁrmed the long-term efﬁcacy of TPM (Tartara et al 1996; Guerreiro et al 1999; Glauser et al 2000; Coppola et al 2002; Mikaeloff et al 2003; Al Ajlouni et al 2005) with improvement in quality of life (QOL) associated with better seizure control (Alva-Moncayo and Ruiz-Ruiz 2003). The overall safety proﬁle makes this drug option appealing when compared to the possible life-threatening adverse events of FBM and LTG. Rapid titration is possible in emergencies, but aggravates central nervous system (CNS) adverse events, including somnolence, mental slowing, fatigue, and ataxia. A slow dose-titration schedule is, therefore, usually necessary to avoid particularly cognitive and language problems worsening with a rapid dose escalation. Weight decrease could be an issue in some children, but can be welcome in others. Unexpected adverse events have been published, such as acute glaucoma (Banta et al 2001) or oligohidrosis (Arcas et al 2001). However, to date, TPM has not been associated with any life-threatening adverse events. 1007