Take home messages:
- A global audit on the treatment of refractory SE and super-refractory SE was launched at the colloquium. Please register at http://www.status-epilepticus.net.
- Clinical trials in status epilepticus are revitalising and improving practice. RAMPART has shown im midazolam to be superior to iv lorazepam as initial treatment, and a trial to compare Valproate, Levetiracetam and fosPhenytoin is planned.
- Basic science advances in microRNA technology and inflammation offer the promise of potential antiepileptogenic strategies in the future.
Status epilepticus: Impressive advances despite the challenges
Status epilepticus (SE), sometimes described as the maximal expression of epilepsy, together with acute seizures represents a significant proportion of acute medical presentations to emergency departments, as well as being a not infrequent complication of numerous neurosurgical, general medical and neurological conditions both in and out of hospital.1 Progress in translating significant advances in scientific knowledge into clinical practice have perhaps been hampered in the past by the fact that the clinicians most interested in the condition, usually epileptologists/neurologists, are often not those most involved in the acute management (emergency physicians, general medical teams, neurosurgeons, anaesthetists, intensivists and paediatricians). Building on the success of three previous SE dedicated conferences (1962, 1980 and 1997) two of the world’s leading authorities in SE, Simon Shorvon (London, UK) and Eugen Trinka (Previously from Innsbruck, now Salzburg, Austria) not only recognised the importance of facilitating true multidisciplinary debate and collaboration to drive progress, but did something about it. Thanks largely to their efforts, supported by the ILAE commission of European Affairs, 344 doctors and scientists from a broad range of backgrounds attended the fourth London-Innsbruck colloquium on SE and acute seizures held in Salzburg in April 2013.
Each of the meetings has been defined by a stated purpose to summarise current knowledge in key clinical and basic science areas, to define optimal clinical practice, to debate controversial issues, and to inform future clinical and scientific areas. Arguably, this is the purpose of any speciality conference, but by explicitly defining this at the outset and allowing considerable programme time dedicated to debate and discussion, together with taking advantage of the opportunity to have the best in the world from a broad range of disciplines focus on specific issues, this meeting has become a “must attend” for anyone working in SE/acute seizures. It also has much to offer educationally for others with an interest. As well as a review of the achievements covered in the three prior colloquia since 2007, particular highlights of the most recent meeting are summarised below.
That the effectiveness of benzodiazepines in terminating SE decreases as SE progresses is now well established in a range of animal models, and also in clinical practice. The molecular mechanisms behind this are increasingly unravelling, including internalisation of GABAA receptors,2 and enhanced AMPA mediated excitatory conductance, possibly due to post-synaptic changes in AMPA receptor expression.3 Whether this will translate into clinical benefits, e.g. a role for AMPA antagonists (at least one, perampanel is now licensed for adjunctive use in refractory epilepsy) in SE remains to be seen.
In a masterful presentation of quite complex science to a largely clinical audience, David Henshall from Dublin summarised work demonstrating changes in specific micro-RNAs (non-coding RNAs which function as post-transcriptional modulators of intracellular proteins) following SE.4 Proteins involved in neuronal structure and excitability, gliosis, inflammation and apoptosis are selectively affected, and of particular interest as a potential antiepileptogenic target (as opposed to anti-seizure as for current Anti-epileptic Drugs, AEDs). Using chemically modified antisense oligonucleotides, Antagomirs, in an animal model of SE, administration of a single dose one hour after SE was followed by a 90% reduction in subsequent spontaneous seizures (post-SE epilepsy) and substantially less structural damage, maintained even in animals studied up to two months later. Whilst there are undoubtedly still several hurdles to overcome before studies in man can be undertaken, this is certainly one of the most promising approaches in pre-clinical development in terms of neuroprotection and antiepileptogenesis in epilepsy.
A particular feature of these meetings has been a themed post-congress closed workshop, bringing together specific individuals to work towards a defined output. Clinical trial design was the focus of a 2009 workshop, informing a proposed Established Status Epilepticus Treatment Trial (ESETT) proposal first outlined in 2011,5 with a funding application now in the final stages of refinement with USA and European collaborators. This hopes to learn from and build on the impressive success of the RAMPART study,6 lessons from which were also reviewed at the meeting. RAMPART completed ahead of schedule, and despite being powered as a non-inferiority study, demonstrated the superiority of intramuscular midazolam over the previous gold standard intravenous lorazepam for the out of hospital initial treatment of SE. That this was named as Trial of the Year by the Society for Clinical Trials is not only a well deserved accolade, but also one hopes the start of a new era for clinical trials in this sometimes devastating condition.
A recurring theme throughout the meeting was the need for increased data sharing between centres, and the need for standardised data collection to facilitate this. This was also the topic of this year’s post-congress workshop, with a global audit on the treatment of refractory SE and super-refractory SE launched at the colloquium, and now underway (http://www.status-epilepticus.net). The methodological flaws inherent in non-randomised observational studies of this nature should at least be partly mitigated by that numbers (>1000 patients over 12 months is the target) should far exceed any achievable in the setting of a clinical trial.
Abstracts from the meeting are available from the congress website at http://www.statusepilepticus2013.eu, and will be published in full in Epilepsia later in 2013. Readers are encouraged to look out for advance notice of the anticipated 5th London-Innsbruck Status Epilepticus Colloquium to be held in April 2015.
- Shorvon, S. The treatment of status epilepticus. Current Opinion in Neurology, 2011;24(2):165-70.
- Naylor, DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci, 2005;25(34):7724-33.
- Rajasekaran K, Joshi S, Kozhemaykin M, STodorovic M, Kowalski S, Balint C, Kapur J. Receptor trafficking hypothesis revisited: Enhancement of AMPA receptormediated neurotransmission during established status epilepticus. Epilepsia, 2013. In Press.
- Henshall, DC. Antagomirs and microRNA in status epilepticus. Epilepsia, 2013. In press.
- Cock HR, obotE group. Established Status Epilepticus Treatment Trial (ESETT). Epilepsia, 2011;52:50-2.
- Silbergleit, R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W. N Investigators, Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med, 2012;366(7):591-600.