Cardiac arrhythmias and SUDEP—Commentary on Hindocha et al.

Discussion of basic mechanisms of the epilepsies constitutes an important part of every epilepsy congress or symposium. Investigators working in the laboratory made significant contributions to the International Epilepsy Congress last July. This article summarizes some of the new insights into the mechanisms of epileptogenesis and the novel strategies for therapeutic intervention emerging from the basic science sessions at the 27th International Epilepsy Congress in Singapore. Each of the following paragraphs also includes the names of those investigators (in parentheses) who presented this material at the Congress. Much emphasis has been given to the role of KCNQ channels and their associated M-currents in providing inhibitory control over neuronal discharges. These channels control the generation and frequency of action potentials, are strategically concentrated at brain regions relevant to epilepsy, and loss of function mutations in KCNQ2/3 channels underlie epileptic seizures in neonates (i.e., benign familial neonatal convulsions). This insight, together with the broad-spectrum anticonvulsant activity of drugs enhancing M-currents in animal models of seizures, suggests that these channels represent novel molecular targets for developing antiepileptic drugs (Y. Yaari, J. Kempfle). Interactions of steroid hormones with seizures were presented with particular attention to the mechanisms involved in the neuroprotective action of β-estradiol (J. Veliskova). Long-term treatment with low doses of β-estradiol delays seizure onset in rats and dramatically reduces seizureinduced hippocampal damage; these effects appear to depend on the ability of β-estradiol to enhance neuropeptide Y levels in hilar interneurons, which in turn leads to increased inhibition in the dentate gyrus. Neurosteroid compounds synthetized within the brain and acting in a nonclassical fashion (via actions that do not involve nuclear hormone receptors) have been described as potent allosteric modulators of GABAA receptors. Fluctuations in neurosteroid levels may contribute to seizure exacerbation at times of stress or in catamenial epilepsy (M. Rogawski). Recent studies show that neurosteroids can retard epileptogenesis following status epilepticus. Ganaxolone, a neurosteroid analog, is currently undergoing clinical trials for the treatment of infantil spasms and adult partial epilepsy. Among the novel targets for seizure inhibition, inflammation and the blood–brain barrier (BBB) have an emerging role: selective inhibitors of inflammatory pathways activated by brain injury or by status epilepticus have been shown to reduce seizures and retard epileptogenesis in various experimental models (T. Ravizza, S. Balosso, Y. Murashima, M. Fukuda); a novel molecular pathway activated by serum components, such as albumin, under conditions of increased BBB permeability may trigger epileptogenesis, via activation of TGF-β receptors (A. Friedman). The data suggest that serum albumin is taken up by astrocytes via TGF-β receptors, leading to down-regulation of Kir-4.1 channels and glutamate transporter, and these events may be involved in the development of epileptiform activity. Targeting of the BBB has also been proposed as a strategy to contrast pharmacoresistance (H.Potschka, L. Chen). Noncompetitive inhibitors of multidrug transport proteins, which are overexpressed in endothelium of brain vessels and the associated astrocitic endfeet in epileptic tissue, enhance the brain levels and the efficacy of phenytoin and phenobarbital in experimental models of drug-resistant seizures. Recently, a pilot functional PET imaging study in pharmacoresistant epileptic patients showed a reduced uptake of verapamil, a P-glycoprotein substrate in the focal epileptogenic area, supporting a functional upregulation of drug efflux activity in the BBB (Langer et al., Epilepsia 2007;48:1774–1784). Gene therapy approaches have been described in models of focal epilepsies using viral vectors expressing neuroprotective peptides (such as NPY or galanin) (F. Noe’, M. Kokaia, M. During), or the GABAA receptor alpha1subunit (A. Brooks-Kayal). Experimental findings report either a decreased risk of developing epilepsy or a strong reduction in spontaneous seizure frequency and the arrest in seizure progression, highlighting the possibility of using gene therapy not only to suppress seizures but also to interfere with epileptogenesis. Imaging studies in experimental models of seizures suggest a predictive value of MRI for the development of epilepsy (J. Jansen, I. Kharatishvili). Quantitative measurements of water diffusion in the rat hippocampus ipsilateral to neocortical fluid-percussion injury (a model of traumatic brain injury) positively correlates with the increased seizure susceptibility developing in rats 12 months postinjury. This correlation could be established as soon