Epileptologists in quest for the Holy Grail

Abstract

The epilepsies affect around 50 million people worldwide and constitute in 2012 the second neurological group of diseases. Anyone can suffer one type of epilepsy with more or less severe repeated seizures independently of age, race, or of socioeconomic or geographic situation. In Europe, the prevalence of epilepsy is of 8.2 per 1,000 corresponding to 6 million individuals with active epilepsy and around 15 million having experienced epilepsy during their lives (see [1]). Since almost two or even three decades now, the epileptologists repeatedly claim that in spite of the scientific progress in the field of basic neurosciences on the one hand and in clinical and neuropharmacological research on the other hand, 30–40 % of their patients remain incurable or at least drug-resistant. It took a long time to recognize the extreme diversity of the epileptic syndromes and to remain concentrated on the treatment of the seizures themselves. One of the symptoms of this is the ongoing use of the term ‘‘Epilepsy’’ in the singular form. For years, this attitude was clearly justified, since the antiepileptic drugs were efficient in at least half of the patients. Therefore, from the clinical point of view, considerable efforts have been developed to better identify and classify new epileptic syndromes and sometimes diseases. Truly, the principal symptom that links the different epileptic diseases is the seizure itself, a phenomenon due to the sudden occurrence in a particular area of the cerebral cortex of an epileptogenic circuit probably starting by hypersynchronous bioelectrical discharges in a set of cortical neurons then propagating in specific parts of the brain through synaptic connections. Therefore, for years, the therapeutic efforts tended to limit excitation and/or to favour inhibition considering epilepsy (i.e. ‘‘in singular’’) as a clear imbalance between these two phenomena. Although several experimental evidences illustrated that one can produce huge epileptogenic circuits by favouring GABAergic inhibitory inputs in some circumstances, one has to observe that this ‘‘old thought’’ is still hard to tackle among the clinical and also the pharmacological world. Since 1995, positional cloning strategies in multigenerational families with autosomal dominant transmission have revealed several genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1...) and numerous loci for febrile seizures and epilepsies. Most of these genes encode neuronal ion channel or neurotransmitter receptor subunits creating a first enthusiastic hypothesis that at least idiopathic generalized epilepsies could be considered as a new group of channelopathies. However, molecular approaches have revealed great genetic heterogeneity, with most genes remaining to be identified. One of the major challenges is now to understand phenotype–genotype correlations. Following these advances, it became more and more popular to think of the antiepileptic treatment in terms of their basic mechanisms of action, i.e. acting on Na or K channels or GABA transmission, etc...., as if a specific and precise molecular mechanism of action in given epileptic syndromes (childhood absence epilepsy, medial temporal lobe epilepsy, or the Dravet syndrome, etc....) were completely elucidated. We have to admit that this probably still constitutes an illusion. Today, the effort to clarify the effectiveness of a rationale of antiepileptic treatment on a (somewhat empirical) clinical basis and multidisciplinary T. Grisar (&) CHU, Department of Neurology, GIGA Neurosciences Research Centre, University of Liege, Liege, Belgium e-mail: tgrisar@ulg.ac.be