Chronic medical treatment “Old” antiepileptic drugs Benzodiazepines (BZDs) BZDs, since their development in the 1970s, remain among the most powerful available AEDs, particularly in SE. They can be divided into two groups: 1,4-BZDs (clonazepam, clorazepate, diazepam, nitrazepam, lorazepam) and 1,5-BZDs (clobazam). The BZDs act on the BZD receptor, as agonists, to potentiate gamma-aminobutyric acid (GABA) neurotransmission, on voltage sensitive calcium channels and on Na+ channels. They reportedly increase the frequency of chloride channel opening and act by suppressing the spread of seizure activity but not by abolishing the abnormal discharge of the epileptic focus. BZDs reduce the inhibitory output of the reticular neurons and, therefore, prevent absence seizure activity. BZDs have been used as acute parenteral or rectal agent (diazepam, lorazepam, midazolam) or for chronic oral use (clobazam, clonazepam, clorazepate, nitrazepam) (Vassella et al 1973; Muller and Lenard 1988; Trimble 2002). BZDs remain, in most guidelines, the treatment of choice for acute or subacute seizures, but should be avoided, particularly the 1,4-BZDs, for prolonged therapy because of tolerance, somnolence, risk of withdrawal seizures, increased bronchial or oral secretions, etc. However, in practice, they are still widely prescribed with the speciﬁc risk in LGS of precipitating tonic SE (Dimario and Clancy 1988). Clobazam (CLB) CLB,theonly1,5-BZD,works,inanimalmodels,byintensifying GABA-mediated inhibitory effects and by increasing the activity of glutamate transporters. CLB is metabolized by CYP3A4 and 2C19 to the active metabolite-N-Desmethylclobazam (NCLB). This BZD presents several advantages over the 1,4-BZDs, especially for add-on therapy, including a: rapid onset of action, broad spectrum of activity, long half-life, and few important drug interactions. Vajda et al (1985) studied the effects of CLB in patients with refractory epilepsy, some of them suffering from LGS; however, it is not possible to analyze the effects on patients with LGS independently of the global results. CLB may have fast and impressive results (Farrell 1986; Munn and Farrell 1993) and is better tolerated than other BZDs. According to the litterature, long-term efﬁcacy can be maintained in 40 to 60% of patients with refractory epilepsy (Ng and Collins 2007). Schmidt and Bourgeois (2000) recommend the temporary add-on use of CLB while modifying or reducing doses of concomitant AEDs. In a Phase 2 trial, CLB signiﬁcantly reduced drop seizures compared to baseline. A phase 3 trial is ongoing Neuropsychiatric Disease and Treatment 2008:4(6) Lennox-Gastaut treatment in patients with LGS (on May 1, 2008: http://clinicaltrials. gov/ct2/results?term=clobazam; clinicaltrials.gov identiﬁer: NCT00518713). In 2008, CLB has been designated as an orphan drug by the FDA for patients with LGS. Clonazepam (CZP) This AED was considered as one of the drugs of choice for the management of myoclonic epilepsies, including LGS (Pinder et al 1976). Unfortunately, tolerance develops in approximately 30% of patients, even after adjustment of dosage. Withdrawal seizures are frequent and sometimes severe in case of irregular intake or (non) accidental withdrawal. Furthermore, CZP may precipitate the occurrence of tonic-clonic seizures and tonic (Tassinari et al 1972, Dimario and Clancy 1988) or absence SE. The most frequent side effects are drowsiness in about 50% of patients and ataxia in approximately 30%. Seizures related to drowsiness may, therefore, be increased. Furthermore, signiﬁcant interactions exist with other AEDs and other common medications, including cimetidine, disulﬁram, oral contraceptives, digoxin, and rifampicin. CZP should, therefore, not be prescribed for chronic use, or only as a last option. Nevertheless, this AED is still often used as a ﬁrst or second option, partly because of its low cost. Clorazepate (CLZ) This BZD is prescribed in refractory epilepsies (Trimble 2002) and some excellent results have been published (Naidu et al 1986), but there are no speciﬁc data for LGS and no controlled data. This BZD is mostly prescribed as a second line AED in focal seizures. Diazepam (DZP), lorazepam (LZP), midazolam (MDL) These BZDs are mainly used for acute, prolonged or cluster seizures and SE. They can be administered intrarectally, by intravenous infusion or, for midazolam, by intramuscular, intranasal or intrabuccal routes (Scott et al 1999). Nitrazepam (NZP) This BZD tends to be used in pediatric epilepsy, speciﬁcally in infantile spasms and LGS. However, only uncontrolled data are available (Chamberlain 1996; Farrell 2002; Hosain et al 2003) and excessive sedation has been described in numerous children. Carbamazepine (CBZ), oxcarbazepine (OXC) These AEDs act mainly by inhibiting the voltage-activated Na+ channels. OXC differs from CBZ by also inhibiting 1005