UC Irvine

Spontaneous seizures are the most overt manifestation of epilepsy, a disorder that affects -1 % of the general population [ Browne and Holmes, 2008; Hesdorffer et al., 2011a; Zack and Kobau, 2017). The seizures, and their unpredictability, lead to decreased quality of life in affected individuals, who are often unable to drive and may experience stigmatization from peers in the community. Temporal lobe epilepsy (TLE), a type of epilepsy involving the hippocampal­limbic circuit, is particularly difficult to treat, and one-third of patients with TLE experience seizures that are refractory to anticonvulsant medication [Schmidt and Loscher, 2005]. TLE often arises in adolescence, leading to decades of decreased quality of life and medical costs. In addition to the overt burden of the seizures themselves, epileptic seizures are frequently accompanied by problems in memory and executive functions that contribute to poor quality of life [Loiselle et al., 2016]. This is particularly a problem in TLE, because the temporal lobe is comprised of many brain circuits that are required for learning and memory function. These cognitive deficits, including memory and decision-making difficulties, often begin while patients are still in school, further hampering their education and future career potential [Helmstaedter et al., 2003]. In fact, whereas the seizures in TLE have been considered the cause of memory problems, recent studies show that memory deficits often arise either before the onset, or independently of spontaneous seizures [Aikia et al., 2001; Chowdhury et al., 2014; Elger et al., 2004; Hoppe et al., 2007; Weiss et al., 2017]. This suggests that cognitive deficits in chronic epilepsy cannot be exclusively interpreted as long-term effects of the seizures or anticonvulsant drugs. In addition to learning and memory related difficulties, children with epilepsy have significantly higher rates of depression (23%) and anxiety (36%) than their healthy peers, and these disorders can appear prior to or within months of the first epileptic seizure (Jones et al., 2007]. TLE most commonly arises in individuals with a history of long childhood febrile seizures or febrile status epilepticus (FSE) [French et al., 1993; Harvey et al., 1995]. An ongoing study, the FEBSTAT study, has been following 199 children from the onset of FSE. This is the first large-scale prospective research on children that combines early brain imaging, cognitive and medical outcome measures. Results from this groundbreaking study, which started in 2002, have recently begun to emerge. It has confirmed previous findings in animal and human studies that FSE directly provokes hippocampal injury [Lewis et al., 2014; McClelland et al., 2016; Provenzale et al., 2008; Shinnar et al., 2012] and memory impairments [Martinas et al., 2012; Weiss et al., 2017]. Here we discuss the emerging evidence that FSE may contribute to both the seizures and the cognitive problems that are often an intrinsic component of TLE.