Status epilepticus—Where are we in 2013?

Authors


Address correspondence to Eugen Trinka, Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz Harrerstrasse 79, A-5020 Salzburg, Austria. E-mail: e.trinka@salk.at

The 4th Colloquium in the series of the London-Innsbruck Colloquia (Shorvon et al., 2007; Trinka, 2009; Shorvon, 2011) was held on April 4–6, 2013, in Salzburg. This supplement contains the summaries of the presentations and the posters. The purpose of the meeting was to summarize the current knowledge and advances in clinical and basic sciences, and to identify future directions in the field of status epilepticus. There were gathered at the conference 367 participants, from 49 countries.

As it becomes evident from the contributions to this supplement, there were fascinating new directions in basic science, including new insights into receptor trafficking of γ-aminobutyric acid (GABA) and glutamate receptors, as well as ion channels. There have been new approaches in the understanding of the mechanisms of status with presentations on microDNA, antagomirs, and the role of adenosine. There have been neurophysiologic advances and insights of status as a system disorder and disturbance of synchronization. Advances in clinical studies include the possibility of gene therapy and the better understanding of the role of inflammatory mechanisms and autoimmunity. Although there have been advances in invasive neuromonitoring, the treatment and the prognosis of super-refractory status remains unsatisfactory. Despite the fact that clinical trials were, at the first London-Innsbruck Colloquium 2007, regarded to be so difficult to conduct as to be probably unrealistic and impractical, landmark prehospital studies have been successfully conducted, and now studies in the established and refractory status are planned or being carried out. In addition, a range of new drugs and approaches of therapy are in the preclinical phase or in early clinical phase II trials.

Despite these advances, the incidence of status remains higher than it should be, and preventative measures are not fully exploited. Approximately 30% of patients with status epilepticus (SE) are not controlled with initial treatments, and the mortality rate is unacceptably high, with 20% dying, and there is also substantial morbidity among the survivors. Although the basic sciences are advancing rapidly on different fronts, it is difficult to know what is truly significant and important in improving patients' treatments and outcomes. Similarly, we do not know the relative importance of different proposed mechanisms in epileptogenesis. In up to 30% of cases of new-onset SE, the cause remains unidentified (Neligan & Shorvon, 2010; Tan et al., 2010; Trinka et al., 2012).

High-class clinical trials remain extremely challenging to perform, especially in refractory SE. This, together with the lack of industry interest, owing to its presumed small business “niche” and the currently inappropriate regulatory requirements, leads to the complete absence of industry-sponsored randomized controlled trials (RCTs) and the low number of academically driven trials. Some of the promising drugs in development tackle a range of novel targets using innovative mechanism and still have to pass the clinical hurdle. The problems in translation from basic science to preclinical testing and then clinical trials are undoubtedly difficult to overcome. A recent green paper of preclinical testing of epilepsy treatments have identified several yet unsolved issues, such as the following: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy (Galanopoulou et al., 2012). New treatments for SE fall into each of these categories, but none of the specific problems in SE have been discussed separately.

Another problem is the inconsistent availability of treatments for SE in many countries around the world. Current first-line treatments are either not licensed or not marketed. Again, the lack of economic interest to introduce drugs, which have been off patent for many years, is limited. In addition, the currently available treatments in established and refractory status are poorly evaluated, and the issue of cause-specific, disease-modifying, and antiepileptogenic treatments has yet to be addressed.

SE causes additional morbidity in acute symptomatic cases, which may worsen outcome. Despite the advances of intensive neuromonitoring and the increasing detection of subclinical or electrographic seizures, proof that intensive treatment of electrographic seizures improves outcome in these patients remains lacking.

The optimal treatment of refractory and super-refractory SE remains far from clear, and no commonly accepted treatment protocol has been established. Discussions at the London-Innsbruck Colloquium resulted in the establishment of an online global audit of treatments in these advanced stages of SE (www.status-epilepticus.net). The audit aims to ascertain what treatments are being used globally in refractory and super-refractory SE in the intensive care setting. The global audit has been devised to gather as much information as possible, and then on this basis to devise guidelines and inform further research.

Disclosure

The authors were co-chairs of the 4th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, but declare no other relevant conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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