Status Epilepticus 2013
The London-Innsbruck Status Epilepticus Colloquia 2007–2011, and the main advances in the topic of status epilepticus over this period
Address correspondence to Simon Shorvon, UCL Institute of Neurology, Box 5, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, U.K. E-mail firstname.lastname@example.org
In this article, the three previous London-Innsbruck Colloquia on Status Epilepticus are reviewed. The background to the colloquia and the range of topics covered in each colloquium are outlined. The areas in which advances in the study of status epilepticus, and also areas in which advances have been disappointing are highlighted.
Three previous London-Innsbruck Colloquia on the topic of Status Epilepticus have been held, in 2007, 2009, and 2011, organized with the support of the International League Against Epilepsy (ILAE) Commission on European Affairs (CEA) under the auspices of University College London and the Medical University of Innsbruck. These conferences were designed to invigorate debate and study on the topic of status epilepticus (SE), much as the first medical conference devoted to the topic (the Marseilles Colloquium in 1962) did, and the further conferences held in Santa Monica in 1980 and 1997. The current series was conceived to be in direct lineage to these landmark events.
The stated purpose of the first colloquium, held in London in 2007, was to summarize current knowledge in key clinical and basic science areas; to define optimal clinical practice; to debate controversial issues; and to point to future clinical and scientific research areas. These remained the four objectives of the next two colloquia: the 2009 conference held in Innsbruck and the 2011 conference held in Oxford. The faculties of all the meetings consisted of clinical academics and basic scientists, with an aspiration to attract the best in the world, and the emphasis of the congresses has been on debate and discussion. A closed workshop has also been held with each meeting on a different aspect of status epilepticus. The proceedings of all the meetings and the first workshop have been published as supplements in Epilepsia (Shorvon et al., 2007, 2008; Trinka & Shorvon, 2009; Shorvon & Trinka, 2011).
Certainly, interest in status epilepticus has grown in the last decade or so. The topic that had been hitherto largely absent from the international ILAE congresses, for instance, has appeared now in all the major annual events. As a sign of interest the growth in literature has been striking. The number of articles listing “status epilepticus” as a keyword on a Medline search, for instance, was 201 in the years 1960–1975, 1,165 in the years 1975–1990, 3,364 in the years 1990–2005, and in the past 6 years 3,355 articles have been published.
The Main Advances in The Field Over the Period 2007–2013
A summary of the topics of the three previous colloquia is shown in Tables 1-3. As is immediately clear, a wide range of subjects has been covered, and it is difficult over the relatively short perspective of 8 years or less to pick out the leading advances that have occurred. The list that follows is inevitably personal and incomplete, and we have divided these into three main categories: molecular and basic science, clinical, and therapeutic. In addition, the outcomes of the three workshops will be highlighted.
Table 1. Topics covered at the 1st London–Innsbruck Colloquium on status epilepticus
|Molecular nature of status epilepticus (SE)|
|Relevance of SE in animals to human SE|
|Changes in GABAA receptors in SE|
|Impact of receptor changes on treatment|
|Inflammation modifies hippocampal injury|
|Influence on brain development|
|Role of genetic influences in animal models|
|Role of mitochondria in SE|
|Gene and protein expression|
|What is nonconvulsive status epilepticus (NCSE)|
|Electroencephalography criteria for NCSE|
|When is epileptic encephalopathy NCSE|
|How urgent is therapy for NCSE|
|Clinical pharmacology of parenteral drugs|
|Valproate and other new antiepileptic drugs in SE|
|Which anesthetic to use in SE|
|Clinical trial design|
|Intensive care management|
|Outcome of SE|
|Endogenous mechanisms of neuroprotection|
|Mechanisms of drug resistance|
|Animal experimentation and new drug therapy|
|Epidemiology of SE|
|Cognitive outcome of SE in adults|
|Outcome in children|
|Risk of epilepsy after SE|
|Out of hospital therapy|
|SE treatment guidelines|
Table 2. Topics covered at the 2nd London-Innsbruck Colloquium on status epilepticus
|Basic physiology of status epilepticus (SE)|
|Endogenous mechanisms of neuroprotection|
|Basic physiology of limbic SE|
|Physiology of epilepsia partialis continua (EPC) and subcortical mechanism|
|Hypothermia and hyperthermia and other systemic changes in SE|
|The receptor-trafficking hypothesis revisited|
|Drug resistance in SE|
|Genetics of SE|
|Basic physiology of burst suppression|
|Developmental and etiologic aspects|
|Why is developing brain more susceptible to SE?|
|Long-term effects of febrile SE|
|SE in the developing brain|
|How useful is electroencephalography and electroencephalography monitoring?|
|SE in resource-poor countries|
|SE in infection and inflammation|
|SE due to paraneoplastic and nonneoplastic encephalitis|
|Uncommon causes of SE|
|SE in tuberculosis and HIV infection|
|SE in other central nervous system infection|
|Treatment and medicolegal aspects|
|Relative value of standard therapies|
|Pharmacodynamic and pharmacokinetic of intravenous antiepileptic drugs|
|New drugs in SE|
|Novel anesthetics in SE|
|Clinical trials in SE|
|Minimum requires for approval of drugs in SE|
|Psychosis and SE: borderland or hidden cause|
|SE in the law courts|
Table 3. Topics covered at the 3rd London-Innsbruck Colloquium on status epilepticus and acute seizures
|Fundamental mechanisms of status epilepticus (SE)|
|Developmental changes in receptors and in neurotransmitters|
|Mitochondrial function and pathology|
|Potentially pathogenic autoantibodies in SE|
|Activity dependent trafficking of GABAA receptors in SE|
|Computational modeling of epilepsy and SE|
|Light activated channels in SE|
|Blood–brain barrier dysfunction in SE|
|Electroencephalography patterns in coma|
|Cellular mechanisms underlining electroencephalography in coma|
|Clinical aspects and current therapy|
|Febrile infection-related epilepsy syndrome|
|Canine SE for early trials|
|Evidence for use of new intravenous antiepileptic drugs|
|ICU complications in SE|
|Anesthetics in SE|
|RAMPART trial (in the U.S.)|
|Prehospital RCT (in France)|
|ESETT trial (in Europe) and its tribulations|
|Future perspectives for therapy|
|Super-refractory SE: therapies and outcomes|
|Neuroanatomy of SE: value of hypothermia|
|Value of antiinflammatory drugs|
|Potential for brain stimulation|
|New valproic acid derivative|
|Mono- vs. polytherapy approaches in SE|
- i.Molecular and basic science:
Major advances include the rapid growth in understanding of:
- The changes occurring in γ-aminobutyric acid (GABA) receptors during an episode of status epilepticus, and in particular the role of trafficking of receptors away from the cell membrane, which may be contributing to the drug resistance that occurs as the status proceeds. In addition, the changes in other receptor types including trafficking of the glutamate receptor to the cell surface and into the synaptic cleft.
- The role of inflammation in the production and maintenance of status epilepticus, both caused by seizure activity itself and also as a cause of seizures.
- The role of mitochondrial mechanisms and the genetic control of mitochondrial mechanisms (both mitochondrial genes and also nuclear genes such as POLG1).
- The basic physiology of status epilepticus and of electroencephalography (EEG) burst-suppression pattern.
The growth in understanding of:
- The EEG patterns of nonconvulsive status and coma
- New autoantibody- mediated diseases (e.g., N-methyl-d-aspartate [NMDA]–receptor encephalitis, or limbic encephalitis associated with antibodies against the voltage-gated potassium channel/leucine-rich, glioma inactivated 1 protein-complex or glutamic acid decarboxylase
- The importance of uncommon causes of status epilepticus
- Epidemiology of status epilepticus and the range of conditions underlying status in resource-poorer countries
- The concept of “super-refractory” status epilepticus and the setting up of audits and registries of its treatment
Major therapeutic advances include:
- The use of benzodiazepines in out-of-hospital situations (especially buccal midazolam, and the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) study of intramuscular midazolam)
- The potential for initial polytherapy in early status.
- The use of valproate, levetiracetam, and lacosamide at the stage of established status epilepticus
- New drugs in the pipeline for use in refractory status epilepticus and studies of nonpharmacologic treatment
In addition to the aforementioned areas in which significant advances have been made, there are other areas in which progress has been slower and more disappointing. The continued lack of understanding of any genetic influences on status epilepticus, and of the developmental aspects of the condition; the lack of practical benefits from computational modeling; and the failure to progress with regulatory aspects of clinical trials, or to improve outcome in refractory and super-refractory status epilepticus.
All three Colloquia hosted closed workshops dedicated to a specific topic. The first workshop at the First London-Innsbruck Colloquium 2007 was devoted to the treatments of status epilepticus and the availability of antiepileptic drugs throughout Europe. There was a striking heterogeneity of both the availability and the use of intravenous antiepileptic drugs. The extensive discussion of the experts led to treatment recommendations, taking into consideration the availability of the drugs of choice in each country (Shorvon et al., 2008).
The Workshop at the Second London-Innsbruck Colloquium 2009 focused on drug trials, their design, and the medicolegal aspects associated with randomized trials in status epilepticus. Indeed, the trial proposed by a core group (Cock et al., 2011) was later refined by a multinational group from the United States and Europe, and is currently under consideration for funding.
The Workshop at the Third London Innsbruck Colloquium in Oxford was dedicated to the classification of status epilepticus. At the same time the ILAE Commission of Classification charged a group of participants at the Oxford Workshop with developing a new proposal for definition and classification of status epilepticus. The new proposal was exposed for the first time at a Forum at the European Congress on Epileptology in London 2012. Therefore, all three workshops had substantial deliverables, which will further help to improve the better diagnosis and treatment of this devastating condition.
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. The authors were co-chairs of the three colloquia described in this article, but declare no other relevant conflicts of interest.