van Rijckevorsel voltage-gated Ca++ channels. CBZ and OXC can control tonic-clonic and focal seizures and reduce tonic seizures, but aggravation of atypical absences and/or myoclonic seizures is common (Delanty and French 1998; Perucca et al 1998; Schmidt and Bourgeois 2000; Dulac 2001). There are no speciﬁc studies with OXC in LGS. Cinromide In preclinical studies, cinromide seems to offer a broad spectrum of action with inhibitory effects like those of phenytoin (PHT) and CBZ but also effects similar to valproate (VPA) and ethosuximide (ESM). In the 1980s, open-label studies (Lockman et al 1980) reported the efﬁcacy of cinromide in the treatment of LGS. The first multi-center double-blind placebo-controlled clinical trial of treatment for LGS was designed (The group of Cinromide 1989) and 73 patients, 2–18 years old (data available only for 56 participants, 26 on study drug) were enrolled. However, the study was terminated prematurely when it was clear that cinromide was not superior to placebo and further development of this drug was stopped. Succinimides Succinimides reduce the low threshold T-type Ca++ currents in thalamic neurons but also decrease the persistent Na+ and Ca++-activated K+ currents in thalamic and layer V cortical pyramidal neurons. More recently, succinimides, particularly ESM have been shown to reduce the elevated glutamate levels present in the primary motor cortex in animals with absence seizures. – Methsuximide has been used as adjunctive treatment of atypical absences, tonic and myoclonic seizures associated with LGS (Browne 1995). However, only anecdotal results are available. – Trimethadione has considerable efﬁcacy against absence seizures. Lennox (1945) emphasized that trimethadione was also effective against the atypical absences and myoclonic and atonic seizures of LGS. This drug is no longer used because of its toxicity. – ESM is considered as a fourth-line and adjunctive therapy in by Schmidt and Bourgeois (2000) for its effects on controlling atypical absences and improving myoclonic and atonic seizures. Phenobarbitone (PB), primidone (PRM) Barbiturates such as PB act as positive allosteric modulators of GABA-A receptors, but in a different way than BZDs. In addition, they also act on other ion channel systems, including Ca++ and Na+ channels. 1006 In a double-blind crossover trial (Vassella et al 1978), VPA was compared with PB in 17 epileptic children with LGS. VPA appeared to be somewhat more effective than PB but the difference was not statistically signiﬁcant. PB may worsen behavioral problems (Delanty and French 1998) in children and has cognitive and sedative side effects. These AEDs should be avoided even though they can control tonic-clonic seizures (Vassella et al 1973; Muller and Lenard 1988). Phenytoin (PHT) PHT, like CBZ, inhibits the voltage-activated Na+ channels but also the ﬂux of Ca++ ions across synaptic and other membranes. PHT can control tonic-clonic seizures and reduce tonic seizures in LGS, but aggravation of atypical absences and myoclonic seizures is common (Schmidt and Bourgeois 2000; Dulac 2001; Sazgar and Bourgeois 2005) and chronic use should, therefore, be avoided. Acute use may be necessary to manage convulsive SE. Valproate (VPA) VPA acts by several mechanisms: It potentiates GABA-ergic inhibitory effects; interacts with the metabolism of gamma- hydroxybutyrate, a metabolite of GABA; suppresses N-methyl-D-aspartate (NMDA)-evoked depolarization; and inhibits Na+ channels. At higher concentrations, VPA may affect calcium and potassium channels (Johannessen and Johannessen 2003). Other potential mechanisms have also been described recently (Xu et al 2007). This broad spectrum AED is considered by most practitioners and authors to be the drug of choice in this multiseizure type syndrome (Wheless et al 2005). However, VPA alone is rarely sufﬁcient and children with polypharmacy are at greater risk of serious hepatic toxicity or pancreatitis. Only one double-blind study (Vassella et al 1978) has been conducted with 17 patients, crossed-over with PB. The results were not statistically signiﬁcant although there was a trend in favor of VPA. Other studies (Jeavons et al 1977) involved patients with a mixture of epileptic syndromes, including LGS, and it is sometimes difﬁcult to extract results speciﬁc to LGS. Moreover, these studies were observational or retrospective. Vigabatrin (VGB) VGB’s main actions are on the GABA-ergic synapse as an irreversible inhibitor of the GABA-degrading enzyme, GABA transaminase. This single mode of action can explain the frequent worsening of seizures in LGS. Published results are variable (Luna et al 1989, Livingston et al 1989), but VGB may aggravate myoclonic seizures (Dulac et al 1991) Neuropsychiatric Disease and Treatment 2008:4(6)