421 About 13% of patients with epilepsy have a history of febrile seizures (FS). Studies of familial forms suggest a genetic component to the epidemiological link. Indeed, in certain monogenic forms of FS, for which several loci have been reported, some patients develop epilepsy with a higher risk than in the general population. Patients with generalised epilepsy with febrile seizures plus (GEFS+) can have typical and isolated FS, FS lasting more beyond age 6 years, and subsequent afebrile (typically generalised) seizures. Mutations associated with GEFS+ were identified in genes for subunits of the voltage-gated sodium channel and the 2 subunit of the ligand-gated GABA A receptor. Screening for these genes in patients with severe myoclonic epilepsy in infancy showed de novo mutations of the 1 subunit of the voltage-gated sodium channel. Antecedent FS are commonly observed in temporal-lobe epilepsy (TLE). In sporadic mesial TLE—characterised by the sequence of complex FS in childhood, hippocampal sclerosis, and refractory temporal-lobe seizures—association studies suggested the role of several susceptibility genes. Work on some large pedigrees also suggests that FS and temporal- lobe seizures may have a common genetic basis, whether hippocampus sclerosis is present or not. The molecular defects identified in the genetic associations of FS and epileptic seizures are very attractive models to aid our understanding of epileptogenesis and susceptibility to seizure-provoking factors, especially fever. Lancet Neurol 2004; 3: 421–30 Febrile seizures (FS) are the most common human convulsive event. They are not thought of as a true epileptic disease 1 but rather as a special syndrome characterised by its provoking factor (fever) and a typical age range of 6 months to 6 years. Although the prognosis is generally very good, people who have had FS have a higher risk of developing spontaneous afebrile seizures, which define epilepsy when they recur. Several genes have recently been linked with specific, monogenic epileptic syndromes. 2 The susceptibility to FS and subsequent epilepsy is commonly regarded as non-specific in terms of epileptic seizures and syndromes, but has proven nevertheless to be a fruitful approach for genetic research. This review focuses on the recent molecular genetic findings that underlie the epidemiological links between FS and epilepsy, and may contribute to our understanding of epileptogenesis. FS and epilepsy: from epidemiological to genetic links A well-known epidemiological association In North America and Europe, prevalence of FS is about 2–5%, 3,4 but estimates of 7–14% were made for Japan 5 and Pacific islands. 6 FS are benign even though a third of the children will have recurrent febrile events. They resolve spontaneously before the age of 6 years and do not typically require antiepileptic drug therapy 7 (panel 1). Strong epidemiological evidence shows, however, that FS are associated with subsequent afebrile or unprovoked seizures. In prospective follow-up studies of large cohorts of children with FS, afebrile seizures occur in 2–7%, which is two to ten times the prevalence in the general population. 8–12 Estimates depend on the length of follow-up. The risk is about 3% by age 7 years, and one study with a longer follow-up showed a risk of 7% by age 25 years. 9 A prospective study of children presenting to paediatric emergency departments with a first FS indicated a higher risk of 6% at only 2 years follow-up. 13 Retrospective studies of patients with epilepsy indicate that 10–15% had previous FS. 14,15 The association differs as a function of the type of epilepsy (panel 2). 16–26 Antecedent FS occur in about 11% of patients with idiopathic generalised epilepsy; there is, however, substantial variation. For the Review Fever, genes, and epilepsy SB, IG-A, RN, GH, EL, and MB are at the Hôpital Pitié-Salpêtrière and RN is also at the Service de Neuropédiatrie, APHP, Hôpital Necker les Enfants Malades, Paris, France. JS is at the Department of Neurology, Fundacion Jimenez Diaz, Madrid, Spain. Correspondence: Dr Michel Baulac, INSERM U 224, “Cortex and Epilepsy”, Faculté de Médecine Pitié-Salpêtrière, 105 Bd de l’Hôpital, 75651 Paris, Cedex 13, France. Tel +33 (1) 42 16 18 11; fax +33 (1) 44 24 52 47; email michel.baulac@psl.ap-hop-paris.fr Fever, genes, and epilepsy Stéphanie Baulac, Isabelle Gourfinkel-An, Rima Nabbout, Gilles Huberfeld, Jose Serratosa, Eric Leguern, and Michel Baulac Neurology Vol 3 July 2004 http://neurology.thelancet.com Panel 1. Characteristics of febrile seizures (FS) Simple (common, typical) FS Occur usually between 6 months and 6 years of age, with temperature typically greater than 38·5°C. Without evidence of intracranial infection, other definable cause, or antecedent of unprovoked seizure Brief generalised, clonic, tonic-clonic, or atonic seizure Usually a single seizure per febrile illness Recurrence in 30 to 40% of cases Benign, do not require prophylactic treatment Other phenotypic forms of FS Complex: focal jerking or deficit, multiple within the same febrile illness period or within its first 24 h, prolonged for 10 min or more, including febrile status epilepticus Frequent recurrences Febrile seizure plus, when persisting beyond age 6 years For personal use. Only reproduce with permission from The Lancet.