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The Proceedings of the Innsbruck Colloquium on Status Epilepticus

2009; Wiley; Volume: 50; Issue: s12 Linguagem: Inglês

10.1111/j.1528-1167.2009.02357.x

1528-1167

Eugen Trinka, Simon Shorvon,

Pharmacological Effects and Toxicity Studies

Status epilepticus (SE) is one of the most common and feared neurologic emergencies. Even today, tonic–clonic SE carries a mortality of approximately 20% and a serious risk of cerebral damage among survivors. Although tonic–clonic SE was recognized as early as 2,500 years ago, it was in 1825 that Calmeil introduced the term "état de mal," the expression used by the inpatients at the Salpetrière in Paris for this complication of epilepsy. The first documented case of an absence SE seems to be described on an ex voto tablet in 1501 in Austria (Wolf et al., 2007). This Innsbruck Colloquium on Status Epilepticus (http://www.innsbruck-se2009.eu) follows on, and in direct lineage from, the London Colloquium (Shorvon et al., 2007). Both these recent colloquia build on the traditions of the Marseilles Colloquium held in 1962 (Gastaut, 1967) and the two Santa Monica meetings on this topic held in 1980 (Delgado-Escueta et al., 1983) and 1997. Although the Marseilles Colloquium set the basis for clinical classification and terminology, the Santa Monica meetings focused on the pathophysiology and the mechanisms involved in brain damage. In 2007, the London Colloquium concentrated on the enormous increase in our understanding of the mechanisms of SE and SE-induced cerebral damage, and the advances in therapy in the last decade. Even today, none of the drugs used in the treatment of SE have been licensed on the basis of a randomized controlled trial (RCT). Moreover, most of the drugs currently in use are not licensed for this indication, or only at inappropriately low doses. One of the achievements of the London Colloquium was to establish treatment recommendations for the various forms of SE and to identify regulatory and medical aspects that require action, in the European context (Shorvon et al., 2008). Both, the London and the Innsbruck Colloquia were held under the auspices of, and had support from, the ILAE Commission on European Affairs (CEA-ILAE). The London Colloquium was also the starting point of a European initiative led by the editors of this supplement to set up a large randomized pragmatic trial. The preliminary protocol for this trial was presented, by Dr. Hannah Cock on behalf of the steering committee, for the first time at a workshop during the Innsbruck Colloquium. The proposed study protocol was discussed intensively by world leading experts, and a broad consensus inter alia on the pragmatic study design was reached among them. This supplement provides the extended abstracts of the 30 platform presentations at the Innsbruck Colloquium, as well, as the abstracts of the submitted posters. Summaries of the workshops will be published separately. The Innsbruck Colloquium was divided into three sections: (1) basic research and clinical neurophysiology, with special emphasis on the developing brain, (2) etiology of SE with a focus on infection and immunology, and (3) emergency treatment of SE and its medicolegal aspects. With the proposed, biologically driven definition of SE as a seizure in which "the natural homeostatic seizure-suppressing mechanisms" fail (Engel, 2006), the fundamental biologic differences between SE and a seizure that stops after 2 or 3 minutes have to be explored in detail. Proteomics offer a new tool to investigate the cellular and molecular changes associated with SE in animal models. The observed changes are complex, involving numerous and diverse pathways, and are not yet understood; however, future research with various preconditioning stimuli may reveal endogenous mechanisms, which could ultimately lead to the development of new treatment strategies. Changes in gene expression may lead to a dynamic state-dependent alteration in ion channels, receptors, cell metabolism, and neuronal connectivity. Experimental SE in animals can model only some specific aspects of the seizing network, and an integration of all different aspects of the applied model is necessary to better understand why some seizures stop earlier than the others. One of the most robust findings in animal experiments over the last years has been the rapid decrement of function and number of available γ-aminobutyric acid (GABA)A receptors. Whether this so-called GABAergic failure, which appears to be due largely to features of receptor trafficking, and receptor reassembly, can be overcome by using two different drugs with different modes of actions immediately at the onset of SE is not clear; nevertheless, this strategy seems biologically plausible. SE in the developing brain may alter excitability long term. In contrast to the previously held notion derived from animal experimentation that the developing brain is less excitable than the adult brain, we have learned over the last years that the opposite is true—and that receptor function undergoes often opposite changes during the development of the human and the animal brain. Traditionally our view on the different etiologies of SE in humans came from a few epidemiologic studies in developed countries. The fact that SE is indeed a global problem with high incidence rates in resource-poor countries, has been neglected for far too long. Moreover, the range of etiology varies considerably throughout the world. Some causes of SE, which are extremely common in Europe and North America, are rare in resource-poor countries, and vice versa. In some countries, central nervous system (CNS) infections such as malaria, cysticercosis, and tuberculosis are leading causes of SE, and are similarly major determinants of prognosis. Although the mechanisms are far from understood, there has been an enormous accumulation of data on the immunologic pathways of epileptogenesis in animals and on the relevance of immunologic mechanisms in humans; these data were the subject of much discussion at the Colloquium. Modeling mechanisms in animal experiments, it is to be hoped, may reveal new treatment strategies in the near future. As pointed out clearly at the London Colloquium, the treatment of SE is characterized by a lack of RCTs and remains mostly empirical. Some of the Colloquium participants felt that it was highly unlikely that this situation will change in the near future, due to European Union regulations for clinical trials in noncompetent persons, and the prohibitively high risks—not to mention the costs—for pharmaceutical companies in sponsoring pivotal trials in SE. It soon became clear at the Innsbruck Colloquium that it was high time that such a trial was set up and initiated. Current class I evidence is available for only the early phase of SE, but at least 20–40% of cases will need further treatment. Intravenous phenobarbital, phenytoin, fosphenytoin, valproate, and (since 2007) also levetiracetam have been used in the second stage treatment of SE. None of the drugs was compared in an adequately powered head-to-head comparison, and the currently available literature reviewed during the Innsbruck Colloquium suggests clinical equipoise, which is also reflected by the European treatment recommendations (Shorvon et al., 2008). Furthermore, newer treatment options with intravenous antiepileptic drugs such as lacosamide are already available and others are on the horizon. Still too many questions remain unanswered. For example: Should we use one or two drug for the initial stage of SE? How aggressively should we treat nonconvulsive forms of SE? What is the impact of innovative treatments such as hypothermia in refractory SE? When should we stop treatment? Is burst suppression the right electroencephalography (EEG) target for treatment of refractory SE? The proceedings of this Colloquium address these and other issues and will hopefully serve as a research agenda for the coming years. The conference and supplement were made possible by financial support from the Commission on European Affairs of the ILAE, and by unrestricted educational grants from UCB and Eisai. We also want to acknowledge the following sponsors and exhibitors for their unrestricted support: AD-Tech/DID Medical GmbH, Desitin Arzneimittel GmbH, GE Healthcare Handels GmbH, Gerot Pharmazeutika GmbH, Janssen-Cilag GmbH, Neurodata GmbH, Novartis Austria GmbH, Pfitzer Corp. Austria, Sanofi-Aventis GmbH Österreich, SOMNOmedics GmbH, and Special Products Ltd. We confirm that we have read the Journal's position on issues involved in ethical publication and affirms that this paper is consistent with those guidelines. Disclosure: ET has received speaker's honoraria from UCB, Eisai, Pfizer, Cyberonics, Gerot, and Desitin; consultancy fees from UCB and Eisai; and research grants from UCB and GSK. SS has received honorarium for lecturing and/or advisory board membership from UCB, Pfizer, Johnson & Johnson, and Eisai.