The proceedings of the First London Colloquium on Status Epilepticus—University College London, April 12–15, 2007

Field: Medicine (Health Sciences)

Status epilepticus (SE) is the most severe and feared form of epilepsy. Even today, tonic–clonic SE carries a mortality of approximately 20% and a serious risk of cerebral damage among survivors. The condition has an ancient pedigree; it was first recorded as a complication of epilepsy 2,500 years ago and case histories have been described sporadically since. However, it was only in 19th century Paris that it was formally named and defined. The modern clinical approach to SE can be said to have dated from a landmark meeting in Marseilles in 1962 (Gastaut et al., 1967). This conference was the first scientific meeting to be devoted to the topic, and the published proceedings were the first monograph on SE. This European conference stimulated some interest in the topic and led to a second landmark meeting held in 1980 in Santa Monica. The proceedings were published and were the first English language monograph on SE (Delgado Escueta et al., 1983). At the Marseilles meeting, clinical aspects were highlighted (the first modern clinical classification was proposed), and at the Santa Monica meeting, there was a new emphasis on the clinical and experimental aspects of the cerebral damage resulting from SE. At both conferences, participants bemoaned the lack of scientific research on the subject of SE, and the meetings heralded an increasing interest in the topic among physicians and researchers. Sessions devoted to SE began to appear at international ILAE meetings, and a further international conference was held in 1997 in Santa Monica. In the past two decades, there has been an enormous increase in understanding of the mechanisms of SE, and significant advances have been made in its therapy. A monograph was written by one of the editors of this supplement (Shorvon, 1994), and there has been a tremendous growth of the scientific literature—over 2,800 entries in PubMed in the past 10 years, compared to 370 between 1945 and 1978 in Index Medicus. In April 2007, a colloquium on SE was held in London (The First London Colloquium on Status Epilepticus). This supplement provides the extended abstracts of the 30 platform presentations at that colloquium, as well as the abstracts of 20 representative posters. The purpose of the meeting was to summarize current knowledge in key research areas and to define future research needs. The meeting included a workshop on the fourth day devoted to the production of a treatment protocol and guideline for consideration by the ILAE European Commission. This conference will be followed by a second colloquium in Innsbruck in 2009 (http://www.innsbruck-se2009.eu) in which some of the questions highlighted in the London Colloquium will be taken further. Indeed, we see the early 21st century as the time when the morbidity and mortality of SE can be curtailed, and hope that these conferences will contribute to meeting this challenge. The colloquium was divided into three sections: basic research, clinical research, and research into treatment. It was clear during the colloquium that the basic science of SE has advanced considerably on a number of fronts, but much is still left unanswered. The colloquium began with a thought provoking attack on the animal models that we presently use to understand not only SE but also epileptogenesis. Modeling a human condition can be fraught with difficulties and often what is achieved is a model of specific aspects of a condition. This problem is further complicated by studies in different strains of mice, which have demonstrated that genetic background has an enormous influence on both the ease of induction of SE and the consequences. Prolonged seizure activity has long been recognized to result in neuronal death, and it was interesting to see how many of the original observations of Meldrum, Olney, and others hold true today (Meldrum & Horton, 1973; Olney, 1986). There have, however, been significant advances in our understanding of the complex mechanisms underlying neuronal death, including insights into endogenous "neuronal death pathways," mitochondrial dysfunction, and free radical formation. Preventing this SE-related neuronal death has been the subject of research since these early observations, but preventing neuronal death does not necessarily prevent the consequences of SE (e.g., cognitive decline, chronic epilepsy). We are, however, getting closer to developing drugs that may modify these post-SE consequences. It is not just neuronal death that occurs during SE, but there are also changes in gene expression; these changes result in SE being a dynamic condition in which there are ongoing and permanent changes in ion channels, receptors, cell metabolism, and neuronal connectivity. One challenge is to understand not only the pernicious, but also the beneficial aspects of this gene regulation. Upregulation of genes following brief insults (such as ischemia or brief seizures) results in protection of the brain from more severe insults as a form of adaptive tolerance. Changes are effected not only through modifications of gene expression, but also through mechanisms that can rapidly alter surface expression of receptors (e.g., GABA(A) receptors) during SE, which in turn may contribute to changes in drug responsiveness. Whether changes in drug transporter proteins also play a role is still unknown, but there is accruing evidence that they seem to be less important than changes in drug targets. Neurogenesis has an important but unclear role to play in the consequences of SE, as newly born neurons can have both favorable and detrimental effects on cognition and network excitability. The mechanisms underlying and the consequences of SE are dependent upon the circumstances in which status occurs. Younger brains seem to be more susceptible to SE, but less likely to suffer the consequences. However, even without overt neuronal damage, SE in developing brains can result in permanent modifications to neuronal circuits. Further, in the presence of inflammation, SE in the developing brain has far greater consequences, emphasizing the importance of etiology. The clinical papers on the second day of the conference were focused on nonconvulsive SE. A new classification was proposed, pointing out the large gray area around the subject with a number of interesting syndromes in which persistent nonconvulsive seizures underpin unusual and perplexing clinical states. This gray area includes some cases of epileptic behavioral disorder and psychosis, some epileptic encephalopathies, and drug-induced confusional states. There were also divergent views expressed about whether the so-called "Myoclonic Status in Coma" in the aftermath of severe anoxic brain damage is a form of nonconvulsive status. The EEG criteria for nonconvulsive status were defined in detail. The differentiation of nonconuvlsive status from epileptic encephalopathies in childhood was another contentious and topical subject. The second main clinical area debated at the colloquium was that of the outcome of SE, both convulsive and nonconvulsive, in adults and in children. Outcome, particularly in terms of ongoing epilepsy, was a contentious topic. It is still unclear whether nonconvulsive, as opposed to convulsive SE, commonly results in significant cerebral damage: obviously, the approach to treatment will depend on this result. The last day opened with an overview of the epidemiology of convulsive and nonconvulsive status. Treatment of SE at the beginning of the 21st century—the age of guidelines and evidence based medicine—is still characterized by the lack of randomized controlled trials, and thus remains mostly empiric. The reluctance of the pharmaceutical industry to engage in a clinical trial facing a mortality of 20% in this condition, as well as the EC regulations for clinical trials in noncompetent persons, make it unrealistic to hope that randomized controlled trials will answer our questions in the near future. Previous landmark studies by Treiman and Leppik (Leppik et al., 1983; Treiman et al., 1998), among others, have shown that quickly administered intravenous lorazepam is the drug of choice to control seizure activity in SE. After failure of the initial treatment, several options are available: intravenous phenytoin, fosphenytoin, valproate and more recently levetiracetam. None of these treatment options has been compared with another in the setting of a randomized controlled trial. Other intravenous formulations like lacosamide will probably be available within the next years. The current state of published experience was reviewed during the London Colloquium and it became clear that the large number of patients included in case series will not provide any clear information about an approach to treatment that allows generation of guidelines for improving outcomes. The treatment of refractory SE was another contentious subject, where open studies and case series are the only source of information to guide treatment. Barbiturates, propofol, and midazolam are the most widely used drugs, and although published experienced is increasing, a gold standard has still to be defined. Other treatment approaches, like NMDA antagonists, ketamine, and nonpharmarmacological treatments of SE like hypothermia or surgery have also been discussed. The ultimate goal of treatment is not only suppression of seizures but also prevention of neuronal death and epileptogenesis, as well as improvement of neuropsychological sequelae after SE. Useful information may be obtained from well-constructed epidemiological studies, like the North London Convulsive Status Epilepticus in Childhood Surveillance Study (Chin et al., 2006). The formation of clinical networks and competence centers, as in other medical areas like stroke research or movement disorders, could facilitate these types of observational trials. The conference was successful it its goal of providing a summary of current knowledge in a variety of areas of SE, and in raising a series of key questions which will form the nucleus of the second conference to be held in Innsbruck in 2009.