handicap at baseline, which could suggest that mental retardation may be a negative prognostic factor for VNS success. Improvement of alertness, even after long term follow-up, (Aldenkamp et al 2002) and QOL have also been described (Frost et al 2001). Cortectomy/lobar disconnection Some case reports have been published with selective cortectomy and sometimes spectacular results have been reported after surgery (You et al 2007a). Some LGS cases may be seizure free or free from disabling seizures after resective surgery (Quarato et al 2002), sometimes completed by subpial transections in the eloquent cortex. However, each case needs a personalized presurgical evaluation, sometimes including invasive video-EEG to ﬁnd the “driver” hemisphere and/or lobe (van Rijckevorsel et al 2006; Vaz et al 2008). From the published cases, the parietal (Angelini et al 1979; Quarato et al 2002) or frontal lobes (You et al 2007a; van Rijckevorsel et al 2006; Vaz et al 2008) are mainly involved in LGS. Gamma-knife Radiosurgery has been used for callosotomy (Pendl et al 1999; Eder et al 2006; Feichtinger et al 2006). Short-term follow-up reports the same amount of seizure reduction as classical callosotomy with a seizure reduction of 60%, especially of drop attacks. Gamma-knife callosotomy seems safer for the early short term, but longer follow-up periods are needed to exclude the risk of secondary brain tumor or radionecrosis. Multiple subpial transection (MST) Multiple subpial transection (MST) is a new approach for epilepsy surgery, ﬁrst described by Morrell et al in 1989. MST can be an alternative to resection/disconnection when the epileptogenic zone transcends critical areas in the brain, and removal of the cortex may result in serious deﬁcits. MST is performed alone in functional areas or in combination with resection, cortectomy, lobe disconnection, etc. This technique is used in Landau-Kleffner and related syndromes and in focal epilepsies. However, anecdotal case reports in LGS suggest that these patients can improve dramatically after such surgery (Spencer et al 2002; Zhao et al 2003; van Rijckevorsel et al 2006; Vaz et al 2008). Deep brain stimulation (DBS) In the last 15 years, several clinical investigators (Velasco et al 1991) have considered stimulation therapy – broadly Neuropsychiatric Disease and Treatment 2008:4(6) Lennox-Gastaut treatment known as DBS – for targeting different subcortical structures such as the anterior thalamic nucleus, subthalamic nucleus, or amygdalohippocampus in patients with refractory epilepsy and rejected for epilepsy surgery. LGS patients, most of the time with a very broad deﬁnition of LGS, were included in some of these studies (Velasco et al 1993; Velasco et al 2006) However, deﬁnitive conclusions regarding the optimal therapeutic target remain to be clariﬁed. The future Neuroprotection Although neuroprotection is successful only against some aspects of a complex cascade of multiple events during the repetition of seizures and the development of epilepsy, it might be a promising option in the treatment of refrac- tory cases. Based on animal studies, some of the newer AEDs show possible neuroprotective activity in epilepsy (Stêpieñ et al 2005). However, to prevent epileptogenesis, interventions need to be directed against the processes implicated in the brain changes that underlie hyperexcit- ability (Dichter et al 2002) and not only in the prevention of neuronal death. Animal studies have focused on SE or post-traumatic epilepsy models. Neuroprotection may not involve standard AEDs, but free radical scavengers to protect against oxidative injury, for example, or NMDA receptor antagonists. In this regard, some papers have demonstrated possible neuroprotective effects of melatonin in the elderly (Han et al 2000) and in epilepsy (Chung et al 2003), as well as an anticonvulsant effect (Peled et al 2001; Yildirim and Marangoz 2006). At the present time, there is no ongoing study of neuroprotection in LGS. Gene therapy Gene therapy is an old dream among epileptologists and neuroscientists (Freese et al 1997). Gene therapy represents, at the present time, an innovative and promising alternative for the treatment of refractory epileptic patients, especially if inaccessible to surgery. Several gene targets could be used to correct the balance between inhibitory and excitatory aspects of epilepsy with recombinant viral vectors (Freese et al 1997) or transduction of neuropeptide genes (Noe et al 2007). Although the proof of concept may have been established, further investigations are required to demonstrate a 1013