Mechanisms of epileptogenesis and potential treatment targets

Summary

Prevention of epileptogenesis after brain trauma is an unmet medical challenge. Recent molecular profiling studies have provided an insight into molecular changes that contribute to formation of ictogenic neuronal networks, including genes regulating synaptic or neuronal plasticity, cell death, proliferation, and inflammatory or immune responses. These mechanisms have been targeted to prevent epileptogenesis in animal models. Favourable effects have been obtained using immunosuppressants, antibodies blocking adhesion of leucocytes to endothelial cells, gene therapy driving expression of neurotrophic factors, pharmacological neurostimulation, or even with conventional antiepileptic drugs by administering them before the appearance of genetic epilepsy. Further studies are needed to clarify the optimum time window and aetiological specificity of treatments. Questions related to adverse events also need further consideration. Encouragingly, the recent experimental studies emphasise that the complicated process of epileptogenesis can be favourably modified, and that antiepileptogenesis as a treatment indication might not be an impossible mission.

Introduction

Epilepsy is one of the world's oldest recognised disorders, first described by Hippocrates in the 5th century BC.¹ At present, around 50 million people worldwide have active epilepsy with continuing seizures that need treatment, and 30% of patients are drug refractory.² Nearly 90% of epilepsy cases are in low-income countries, and in India, for example, the total cost for an estimated 5 million cases of epilepsy has been shown to be equivalent to 0·5% of the gross national product.² Europe has been estimated to have 6 million patients with active epilepsy, and the annual European health costs associated with epilepsy are over €20 billion.³ In addition to the cost, the social burden associated with the disease and the two-to-three-times increased risk of death mean that there is an urgent need to find ways to prevent the disease in individuals at risk.

Currently, the most efficient ways to prevent epileptogenesis are genetic counselling or prevention of primary epileptogenic injury, for example, by wearing a helmet while riding a bike. In 2011, the prevention of epilepsy in patients at risk after acquired injury remains an unmet medical need worldwide. However, there have been recent developments in the modelling of epileptogenesis after genetic or acquired conditions in mice and rats, which increase the clinical relevance of these models. By use of these animal models, large-scale molecular profiling studies have provided clues to the mechanisms that can contribute to formation of seizure-generating (ictogenic) neuronal circuits. Finally, several laboratories have made attempts to target these mechanisms in clinically relevant experimental study designs, and some of these have shown favourable antiepileptogenic effects. We review and discuss these studies to identify unsolved problems needing attention before the current proof-of-principle studies are taken to preclinical antiepileptogenesis trials or even to the clinic.