van Rijckevorsel Treatment is rarely effective and the ﬁnal prognosis remains poor in spite of new therapeutic strategies, with persistent seizures, mental retardation/deterioration, and behavioral problems. Epidemiology-etiology LGS is rare, with an annual incidence of 0.2–2.8/10,000 births in European countries (Heiskala 1997) but the prevalence of LGS is higher (5% of all epilepsies and about 10% of childhood epilepsy) because of its refractory characteristics (Trevathan et al 1997). LGS can appear de novo in cryptogenic cases (about 30%) or be the result of brain injury of various etiologies (pre- or peri-natal insult, infection, various malformations including dysplasia, and brain tumor) in symptomatic cases. In these latter cases, LGS is often (18%–50%, mean 30%) preceded by West syndrome or focal seizures (Glauser 2004). LGS starts between 2 and 8 years (peak 3–5 years), slightly later in cryptogenic cases than in symptomatic ones, and is more common in boys than in girls. The age-related link suggests an inﬂuence of brain maturation on symp- toms and disease evolution. Indeed, the usual age of onset corresponds with maturation of the frontal lobes and most of the clinical and EEG signs have a frontal lobe semiology. Recently, a defect in the mitochondrial chain has been suggested as the cause of LGS (Lee et al 2008) and this metabolic pathway should be carefully explored in the so-called cryptogenic cases. Diagnosis LGS is characterized by an electroclinical triad: Multiple seizure types, speciﬁc EEG pattern and mental slowing and/or regression. However, etiological diagnosis and identiﬁcation of co-morbidities are important for correct global management. Clinical features The ﬁrst clinical sign, at least in cryptogenic cases, is often the occurrence of abrupt falls. These are followed by intractable generalized seizures, including myoclonic, tonic, atonic, and atypical absences and by mental slowing then regression. Some patients may have tonic and/or non-convulsive status epilepticus (SE). These episodes of SE may aggravate or precipitate cognitive decline. The most disabling seizures are falls, sometimes called “epileptic drop attacks” and may be secondary to atonic or tonic seizures and, more rarely, to myoclonic or 1002 myoclonic-atonic seizures, these being more typical of Doose syndrome. The causes of these epileptic drop attacks are difﬁcult to differentiate clinically and they can result in recurrent injuries and additional handicap. The frequency of drop attacks has been used as the primary outcome in most randomized studies in LGS. Tonic seizures may appear with variable severity from subtle symptoms to generalized stiffness and falls and may be triggered or worsened by benzodiazepines (BZDs) (Tassinari et al 1972; Dimario and Clancy 1988). Atypical absences are characterized by an alteration in, rather than a loss of, consciousness. They may be accompanied by other subclinical signs, such as discreet loss of tonus, subtle myoclonus, head nodding. Myoclonic seizures in LGS are considered rare by some authors but as an important and difﬁcult to treat part of the syndrome by others. However, if this type of seizure is predominant, an alternative diagnosis should be suspected. These seizures may be aggravated by some antiepileptic drugs (AEDs) (Feucht and Brantner-Inthaler 1994). Fewer than 50% of patients have focal seizures and, globally, tonic-clonic seizures are rare (Dulac 2001), although, again, other authors consider them as frequent and resistant to medical treatment. Patients with LGS will have at least one episode of status epilepticus in their history, mainly atypical absence status or tonic status with subtle signs. Some AEDs can precipitate status, especially benzodiazepines (BZDs) (Tassinari et al 1972). Non-convulsive status epilepticus (NCSE) occurs in more than 50% of patients. Typically, NCSE appears as subcontinuous atypical absences repeatedly interrupted by brief tonic seizures or as subtle tonic status with progressive reduction of motor manifestations and prolonged obtundation with mild myoclonias. Progressively, after seizure onset, slowing or arrest of cognitive development occurs with behavioral problems in about 50% of cases, including hyperactivity, aggressiveness, autistic traits. These features are more marked in early onset or symptomatic LGS. Neurological examination is non specific, from normal to lateralized, depending on the underlying etiology. Later in the disease, it can be difﬁcult to differentiate problems related to LGS, from those occuring as a result of AEDs, or because of numerous falls or frequent SE. Teenagers with a history of LGS may continue to have atypical absences, generalized tonic-clonic seizures and atonic Neuropsychiatric Disease and Treatment 2008:4(6)