Review article Neurobiological and physiological mechanisms of fever-related epileptiform syndromes Sebastian Schuchmann a,b , Sampsa Vanhatalo c , Kai Kaila a,d, * a Department of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland b Neuroscience Research Center, Charite ´ – Universita ¨ tsmedizin Berlin, Berlin, Germany c Department of Clinical Neurophysiology, Children’s Hospital, Helsinki University Central Hospital, 00029 HUS, Finland d Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland Received 24 July 2008; received in revised form 30 October 2008; accepted 4 November 2008 Abstract Febrile seizures (FS) are the most common type of convulsive events in children. FS have been extensively studied using animal models, where rat and mice pups are placed in a hyperthermic environment. Such work has largely focused on the consequences rather than on the mechanisms of experimental febrile seizures (eFS). We have recently shown that eFS are preceded by a dramatic rise in the rate of respiration. The consequent respiratory alkalosis affecting the brain and increasing neuronal excitability is a direct cause of the eFS [1]. If a similar mechanism contributes to human FS and other fever-related epileptiform syndromes, a number of factors operating at the molecular, cellular and systems level that have not been previously thought to be involved in their etiology must be considered. These include physiological and pathophysiological factors affecting CO 2 chemosensitivity as well as cellular and systemic mechanisms of acid-base regulation. Furthermore, a critical role for brain pH in FS points to novel types of suscep- tibility genes, which include genes coding pH-sensitive target proteins (e.g. neuronal ion channels) and pH-regulatory proteins. We will discuss these novel ideas and putative therapies based on them. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Febrile seizure; Hyperventilation; Respiratory alkalosis; pH; Carbon dioxide; Human; Rat; Hyperthermia; Interleukins 1. Introduction Febrile seizures (FS), or febrile convulsions, are defined by the ILAE (International League against Epi- lepsy, http://www.ilae.org/) as an epileptic seizure ‘‘occurring in childhood after age 1 month, associated with a febrile illness not caused by an infection of the CNS, without previous neonatal seizures or a previous unprovoked seizure, and not meeting criteria for other acute symptomatic seizures” [2]. The majority of FS take place between 6 months and 5 years of age, peaking at 16–18 months [3–5]. The prevalence of FS varies between 2 and 8% depending on geographical and cul- tural factors, and also on differences in ascertainment definitions and methods [6–8]. FS are mainly generalised tonic–clonic seizures and only 4–16% of the cases show focal characteristics [9,10]. In more than two-thirds of the affected children, FS last less than 10 min, and in 9% the duration is prolonged (>15 min) and a febrile status epilepticus (usually defined on the basis of dura- tion >30 min) occurs in 5% of children [11]. FS are clas- sified as simple FS, which consist of a generalised convulsive seizure without focal neurological features, lasting less than 15 min and not recurring within 24 h, and complex FS which are characterized by a prolonged 0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.11.011 * Corresponding author. Address: Department of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland. Tel.: +358 9 19159860; fax: +358 9 19159810. E-mail address: kai.kaila@helsinki.fi (K. Kaila). www.elsevier.com/locate/braindev Brain & Development 31 (2009) 378–382