Do seizures and epileptic activity worsen epilepsy and deteriorate cognitive function? *Giuliano Avanzini, †Antoine Depaulis, ‡Alberto Tassinari, and *Marco de Curtis *Department of Neurophysiology, IRCCS Foundation Neurological Institute Carlo Besta, Milano, Italy; †Grenoble - Institute of Neurosciences University, Joseph Fourier, INSERM U836, Dynamics of Epileptic Synchronous Network Team, Grenoble, France; and ‡Department of Neurological Sciences, University of Bologna, Bologna, Italy SUMMARY Relevant to the definition of epileptic encephalop- athy (EE) is the concept that the epileptic activity itself may contribute to bad outcomes, both in terms of epilepsy and cognition, above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time. The review of the clinical and experimental evidence that seizures or interictal electroenceph- alography (EEG) discharges themselves can induce a progression toward more severe epilepsy and a regression of brain function leads to the fol- lowing conclusions: 1 The possibility of seizure-dependent worsening is by no means a general one but is limited to some types of epilepsy, namely mesial temporal lobe epilepsy (MTLE) and EEs. 2 Clinical and experimental data concur in indi- cating that prolonged seizures/status epilepticus (SE) are a risky initial event that can set in motion an epileptogenic process leading to per- sistent, possibly drug-refractory epilepsies. 3 The mechanisms for SE-related epileptogenic process are incompletely known; they seem to involve inflammation and/or glutamatergic transmission. 4 The evidence of the role of recurrent individual seizures in sustaining epilepsy progression is ambiguous. The correlation between high seizure frequency and bad outcome does not necessarily demonstrate a cause–effect relation- ship, rather high seizure frequency and bad out- come can both depend on a particularly aggressive epileptogenic process. 5 The results of EE studies challenge the idea of a common seizure-dependent mechanism for epi- lepsy progression/intellectual deterioration. KEY WORDS: Epileptogenic process, Epilepsy progression, Sleep disruption, Kindling, Status epi- lepticus. Epileptic encephalopathies (EEs) are defined as condi- tions in which cognitive, sensory, and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures and/or interictal paroxysmal activity (Dulac, 2001). The definition embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time (Berg et al., 2010). In this section we review the clinical and experimental evidence that epileptic activity, either ictal or interictal, can per se induce a progressive worsening of epilepsies: both seizure frequency/severity and regression of brain function. Clinical Evidence of Epileptic Activity– Related Deterioration It is worth noting that most patients with epilepsy do not have a progressive disorder, as in both seizure worsen- ing and intellectual decline. Indeed, many types of human epilepsies are known that do not progress despite seizure repetition: benign rolandic and occipital epilepsies, absence epilepsies, juvenile myoclonic epilepsy, benign familial neonatal and infantile seizures, and autosomal dominant nocturnal frontal lobe epilepsy, among the most common ones. Therefore, the hypothesis of a progressive Address correspondence to Giuliano Avanzini, Department of Neuro- physiology, IRCCS Foundation Istituto Neurologico Carlo Besta, Via Celoria 11 – 20133 Milano, Italy. E-mail: avanzini@istituto-besta.it Wiley Periodicals, Inc. © 2013 International League Against Epilepsy 14 Epilepsia, 54(Suppl. 8):14–21, 2013 doi: 10.1111/epi.12418 EPILEPTIC ENCEPHALOPATHIES