Ten other patients, aged 28–48, with generalized epilepsy , including four with LGS were given LEV as compassionate use in a pilot prospective study. There was a mild or no effect on seizure reduction (Weber and Beran 2004). Labate et al (2006) studied the effect of LEV in 35 patients with refractory epilepsy, including two with LGS: seizure frequency improved in one and worsened in the other. Pyridoxine (vitamin B6) Since the initial description of this disorder in 1954, pyridoxine-dependent seizure has been recognized as a rare cause of refractory autosomal-recessive seizures in neonates. Diagnosis may be more difﬁcult in later onset cases when other seizure types have been described, including brief focal, atonic and myoclonic seizures or infantile spasms. Pyridoxine and pyridoxal phosphate have then been tested in the treatment of West syndrome and other conditions. Furthermore, Lee et al (2008) reported cases of LGS (25%) in patients with atypical mitochondriopathies and pyridoxine belongs to the so-called “mitochondrial coktail supplement” (vitamins B, C, E, coenzyme Q10 and L-carnitine). Pyridoxine, alone or as part of this cocktail, could be tried in refractory patients with cryptogenic LGS. In their assessment of LGS therapies published in 2000, Schmidt and Bourgeois (2000) already considered the use of pyridoxine as a fourth-line treatment. Sulthiame (STM) STM, already used as early as the 1960s (Garland and Sumner 1964), is a carbonic anhydrase inhibitor responsible, at least partly, for beneﬁcial effects on epileptiform activity secondary to intraneuronal acidosis. It has been used in West syndrome with some success. Reports on its use in myoclonic epilepsies and as a sole AED are few and inconclusive, but in LGS, STM appears to be an efﬁcacious adjunct to currently-used agents (Lerman and Nussbaum 1975), at least in older studies. More recent use of STM is reserved to continuous SW during sleep syndromes and some idiopathic focal epilepsies. Indeed, one possible mechanism implicated in the development of cognitive deﬁcits is a pathologic enhancement of physiologi- cal apoptotic neuronal death in the developing brain. Animal studies show that STM may signiﬁcantly enhance neuronal death in the developing rat brain (Manthey et al 2005). STM has the potential to precipitate acute psychotic episodes, especially in predisposed patients (Liske and Forster 1963). Therefore, continuous follow-up and careful use of this drug Neuropsychiatric Disease and Treatment 2008:4(6) Lennox-Gastaut treatment remain mandatory, especially in the pediatric population, although it is largely considered as safe. Thyrotropin-releasing hormone (TRH) TRH may act as an antiepileptic through a kynurenine mechanism, given that kynurenic acid acts as an antagonist on the NMDA receptor complex; however, the exact mechanism of action remains uncertain. TRH has been successfully used for treating neurologic disorders, including epilepsy with some success. To conﬁrm this antiepileptic effect, 190 participants were included in an open-label, dose-ﬁnding, randomized study; 98 of the patients, 2 years old, had a diagnosis of LGS. Forty-eight of the patients received a low dose of 0.4 mg/kg/day of TRH DN-1417 and were compared to 50 patients treated with the high dose of 1.6 mg/kg/day for 8 weeks. There was no signiﬁcant treatment effect for high dose TRH and no reported discontinuations due to adverse events (Inanaga et al 1989). Tiagabine (TGB) TGB is a selective competitive inhibitor of GAT1 that prevents GABA uptake. By slowing the reuptake of GABA, TGB prolongs inhibitory postsynaptic potentials. In preclinical studies, TGB increases the amount of time with SW discharges in absence models but shows some antiepileptic and neuroprotective effects in status models. It has been shown to be effective in focal seizures but non-convulsive SE and its very narrow spectrum limits clinical use, especially in LGS. Zonisamide (ZNS) ZNS is a broad-spectrum AED with a mechanism of action apparently based on its ability to block voltage-gated Na+ and T-type calcium channels. It shows a modest inhibitory effect on carbonic anhydrase probably unrelated to its antiepileptic action. It has been licensed as adjunctive treatment for focal seizures in adults. Anecdotal improvement has been reported when ZNS is used as add-on therapy in pediatric epilepsy (Santos and Brotherton 2005) and in refractory LGS (Peters and Sorkin 1993; Glauser and Pellock 2002; You et al 2008a). Yagi (2004) analyzed the efﬁcacy of ZNS in 132 patients with LGS from pooled data grouping 1008 patients from controlled and uncontrolled Phase II and III studies and 726 from postmarketing studies: 32% of the patients had a 50% seizure reduction. The most frequent adverse events were drowsiness, ataxia, loss of appetite or gastrointestinal symptoms and slowing of mental activity. 1009