van Rijckevorsel handicapped with a progressive deterioration in IQ, and more than 80% continue to experience seizures throughout life; tonic seizures tend to be prominent over time for some authors, while for others tonic-clonic or atonic seizures, or atypical absences persist. Psychiatric and behavioral problems with autistic features are common and sometimes require intensive treatment. Mechanisms of deterioration have been proposed (Blume 2004) but remain hypothetical. The mortality rate is high, but varies in the literature from about 3%–7%, mostly related to accidents (Glauser 2004), to 25% due to underlying neurological conditions (Camﬁeld and Camﬁeld 2007). Recently, Yamatogi and Ohtahara (2006) reported on the long-term evolution of severe epileptic encephalopathies, and suggested a new syndrome, the “severe epilepsy with multiple independent spike foci” as the ﬁnal evolution of LGS. Data on evolution and prognosis are, however, often contradictory, mainly due to different deﬁnitions of LGS not only over time but also in different countries. Treatment Chronic medical treatment remains disappointing and only six randomized double-blind controlled trials (The group of Cinromide 1989; Inanaga et al 1989; Felbamate study group 1993; Sachdeo et al 1999; Motte et al 1997; Glauser et al 2000) have been published; of these, 4 gave signiﬁcant results (Table 1). Other randomized controlled studies have been published in patients with refractory epilepsy, some of them suffering from LGS, but individual results cannot be extrapolated from the global data (Battaglia et al 1991; van Rijckevorsel et al 1994). Treatment of the multiple seizure types often requires broad spectrum AEDs and/or polypharmacy. AEDs that are effective for one seizure type may worsen another or provoke SE. Furthermore, there is no speciﬁc experimental model for syndromes such as LGS, and rodent models cannot mimic the complexity of LGS for effective drug development (Jensen 2006). Co-morbidities often necessitate speciﬁc treatments, eg, psychotropic drugs, which may secondarily aggravate seizures. In addition, seizures are often very frequent and difﬁcult to count because most are subtle. The seizures may also be difﬁcult to classify (tonic versus atonic or tonic-clonic) and slow disease ﬂuctuations over several weeks or months may occur independently of drug treatment. For these reasons, there may be considerable inter-observer differences in reporting of the numbers and types of seizures in individual patients, which may inﬂuence study results and analysis over the relatively short-term evaluation of clinical studies (average of 3 months). Occasionally surgery, eg, corpus callosotomy, vagus nerve stimulation (VNS) (Patwardhan et al 2000) or resection of an underlying focalized lesion, may be beneﬁcial, and non-AED medical treatments, eg, ketogenic diet or research treatments such as deep brain stimulation (DBS) (Velasco et al 1991) or intraveinous immunoglobulin (IVIG) (van Engelen et al 1994b; Duse et al 1996; van Rijckevorsel 1999), may offer some improvement in selected cases. Table 1 Comparison of double-blind, randomized, placebo-controlled studies in LGS Authors Patients Study design FBM study group 73* participants (37 FBM) Placebo controlled multicenter 1993 Jensen 1994; ﬁnal results for 50 (28 FBM) randomized duration: 70 days Delanty and French age: 4–36 years 45 mg/kg/day 1998 or 3600 mg/day Motte et al 1997; 179* (79 LTG) results Multicenter randomized Delanty and French for 169 (78 LTG) age: 3–25 years double-blind placebo 1998 controlled duration: 16 weeks Sachdeo et al 1999 Glauser et al 2005 112 participants results for 97* (48 TPM) seizure onset age 1–30 years 138* patients (74 RUF) Age : 4–37 years multicenter, randomized double-blind, placebo-controlled duration: 11 weeks Multicenter, double-blind, placebo controlled * = broad deﬁnition. Abbreviations: FBM, felbamate; LGS, lennox-gastaut syndrome; LTG, lamotrigine; RUF, ruﬁnamide;TPM, topiramate. Results 19% total seizure reduction (37 FBM) 34% atonic seizure reduction (37 FBM) 44% atonic seizure reduction in the 28 FBM patients 34% median major type seizure reduction 32% median total seizure reduction 37.3% of 50% RR for drop attacks 33% have a 50% seizure reduction 14.8% median seizure reduction 20.6% total seizure reduction 42.5% median seizure reduction and for RR for tonic-atonic seizures 53.4% with improvement in seizure reduction 1004 Neuropsychiatric Disease and Treatment 2008:4(6)