van Rijckevorsel Ruﬁnamide (RUF) RUF is a novel compound with anticonvulsant activity, a triazole derivative structurally unrelated to currently marketed AEDs, and of largely unknown mechanisms of action (Arroyo 2007; Kluger and Bauer 2007). RUF probably acts by an inhibition/modulation of Na+-dependent action potentials in neurons and by inhibitory effect at the GluR5 subtypes at high concentrations (Perucca et al 2008). The protective index of RUF, in animals, is much higher than that of most common AEDs. RUF has a broad spectrum of anti-epileptic actions including focal and generalized seizures. RUF is extensively metabolized by non-CYP450 systems. The most commonly reported adverse effects are CNS related (headache, somnolence, fatigue and tremor). Randomized, placebo-controlled trials in the 1990s showed efﬁcacy against focal seizures. The development of RUF for neuropathic pain and epilepsy was stopped by Novartis in 2001. This drug was further investigated in LGS in a single (Hakimian et al 2007) and a double-blind (Glauser et al 2005), randomized, placebo-controlled study which showed a statistically significant efficacy in reducing seizures associated with LGS: there was a 42.5% median seizure reduction and 42.5% of responders ( 50% seizure reduction) for tonic-atonic seizures, while 53.4% of patients had some reduction in seizure frequency. Antiepileptic and other drugs used “off label” in LGS Acetazolamide Acetazolamide, a carbonic anhydrase inhibitor, is known to have efﬁcacy against multiple types of seizures and is usually well-tolerated (Lombroso et al 1956; Holowich and Thurston 1958; Lombroso and Forsythe 1960). Acetazolamide could, therefore, be useful as add-on therapy in LGS. However, newer and more powerful AEDs, such as TPM, also inhibit carbonic anhydrase, making acetazolamide less interesting. Allopurinol (ALL) Some reports in the “older” literature suggested an antiepileptic effect of the xanthine oxidase inhibitor, ALL, when added to traditional drugs (Marrosu et al 1990). Six patients with LGS, from 41 epileptic non-hyperuricemic subjects, aged 2–54 years, already medicated with 2 or 3 AEDs were treated with ALL in doses ranging from 150 to 300 mg daily (DeMarco and Zagnoni 1986). A progressive decrease in the weekly seizure frequency was observed in two-thirds of the cases in this open-label study. Further efﬁcacy has never been proven. 1008 Bromide Bromide, introduced in 1857, was, in fact, the ﬁrst effective antiepileptic agent, long before the discovery of PB in 1912. The mechanisms of action are largely unknown but bromide could act via GABA-activated chloride channels, leading to stabilization and decreased sensitivity to epileptic foci. The major problem with bromide is in obtaining a positive balance between seizure suppression and the occurrence of adverse events. After the introduction of newer AEDs, bromide was largely forgotten. In the 1990s, it was tested again in several severe seizure disorders, including LGS (Woody 1990). Results were encouraging, but studies were only short term and without a control group. This drug is still used in catastrophic epilepsies, such as malignant migrating partial seizures in infancy or Dravet syndrome (Tanabe et al 2008), with inconsistent results. Flunarizine (FLN) FLN, a calcium channel blocker, was shown to have electrophysiological effects in vitro in the late 1980s, suggesting anticonvulsant efﬁcacy. In the early 1990s, FLN was tried in a few difﬁcult-to-treat epilepsy patients with some success. One placebo-controlled, cross-over study (Battaglia et al 1991) looked at the effect of FLN in 20 patients with refractory epilepsy, 6–18 years old, 10 of whom had LSG. Thirteen patients completed the study with a 30%–60% reduction in seizure frequency. This drug is no longer used in epilepsy. Gabapentin (GBP) and pregabalin (PRG) GBP synthesized as a GABA-ergic drug does not interact with the GABA receptors but is a ligand of the α2δ voltage-activated Ca++ channels resulting in inhibition of glutamate release at excitatory synapses. PRG is an analog of GBP with the same binding afﬁnity. The clinical proﬁle of GBP in epilepsy patients is restricted to the treatment of focal seizures, with or without secondary generalization. It has been tried in other syndromes and Vossler (1996) reported a worsening of seizures when using GBP in LGS. There is no study of PRG in LGS but this AED may provoke myoclonus (Modur and Milteer 2008). Levetiracetam (LEV) SV2A, a synaptic vesicle protein, has recently been identiﬁed as the likely target of LEV, making this a new and unique mechanism of action among the AEDs (Kaminski et al 2008). LEV was added-on in 6 patients with LGS in a retrospective survey (De Los Reyes et al 2004). Myoclonic seizures were the best controlled while tonic seizures remained unchanged. Irritability was the most common adverse event. Neuropsychiatric Disease and Treatment 2008:4(6)