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Keywords:

  • Status epilepticus;
  • Treatment;
  • Refractory;
  • Super-refractory;
  • Registry;
  • Global audit

Summary

  1. Top of page
  2. Summary
  3. Disclosure
  4. References

There is a remarkable dearth of information about the various therapies used, often widely so, to control refractory or super-refractory status epilepticus despite its high mortality and morbidity. As pointed out by recent literature reviews, there are no controlled studies, and information is based almost entirely on open, often small and retrospective, case series or case reports. Randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available. For this reason, we proposed an international case registry of therapies used in refractory and super-refractory cases and their outcome. Clinicians from different countries will be asked to complete an online questionnaire when they treat a patient with refractory or super-refractory status epilepticus. Information gathered from this database will summarize the spectrum of etiologies, treatments, and outcomes of this challenging condition and may even form the bases for treatment guidelines or future targeted treatment trials.

Tonic–clonic status epilepticus is an important neurologic emergency potentially associated with significant mortality and morbidity rates. Immediate treatment is required, aimed at stopping seizures largely in order to avoid cerebral damage and other morbidity.

The treatment of the earlier phases of tonic–clonic status epilepticus has been well studied and discussed in recent years. There are a number of similar guidelines and protocols published: All contemporary protocols take a staged approach to treatment. Typically, in the early stage of status epilepticus, therapy is with benzodiazepines. If seizures continue despite this therapy, the patient is said to be in stage 2 (established status epilepticus) and therapy consists of intravenous antiepileptic drugs such as phenytoin, phenobarbital, or valproate. Although based on an inadequate evidence base, these stages of treatment are widely accepted and practiced.

If seizures continue despite this treatment for up to 2 h, the patient is said to be in refractory status epilepticus, a stage where general anesthesia is required. However, there are no comparative trials, and the anesthetic is usually chosen on the basis of the prior experience and usual practice of the intensive care unit medical team, at a dose that results in electroencephalography (EEG) burst suppression (a level of anesthesia at which most seizure activity is controlled). In most patients, this treatment regimen is sufficient to control the seizures. In some though, seizures continue or recur. Super-refractory status epilepticus is defined as status epilepticus that continues or recurs ≥24 h after the onset of anesthetic therapy, including those cases that recur on the reduction or withdrawal of anesthesia. It was a term first used in the Third London-Innsbruck Colloquium on status epilepticus held in Oxford on 7–9th April 2011 (Shorvon & Trinka, 2011).

Although constituting a minority of cases of status epilepticus, approximately 15% of patients presenting to a hospital in status epilepticus are refractory (Novy et al., 2010). Refractory and super-refractory status epilepticus are serious conditions and appropriate therapy of these cases is poorly studied.

The mortality rate is substantial, reported in various series between 30% and 50%. Yet, despite the fact that it remains an important clinical problem in all neurology centers worldwide and that all neurologists and intensivists are likely to be involved with the care of patients with refractory and super-refractory status epilepticus, for many therapies there is a remarkable lack of published data concerning effectiveness, safety, or outcome.

A great number of therapies are in current usage and the literature reporting these therapies has been reviewed recently (Shorvon & Ferlisi, 2011; Ferlisi & Shorvon, 2012). One hundred eighty papers were found, and they form the evidence base for therapy. The therapies reported include thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anesthetics (isoflurane and desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, and levetiracetam), hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy (ECT), cerebrospinal fluid (CSF) drainage, vagus nerve stimulation, and deep brain stimulation. It is salutary to note that there is only one randomized or controlled study of any of these therapies (a trial comparing thiopental and propofol) requiring 150 patients for adequate power but which managed to recruit only 24 patients and therefore failed to reach any conclusions (Rossetti et al., 2011). Apart from this study, the evidence base consists entirely of single case reports or small series. Furthermore, none of the widely recommended drugs or procedures has been subjected to an adequate systematic review, despite their adoption worldwide. This is an unsatisfactory state of affairs.

Assessing outcome of individual therapies is even more difficult owing to the complete lack of controlled data, the fact that all super-refractory patients are on multiple therapies, the tendency for authors to report effect days after the therapy is started and which can therefore be difficult to securely attribute to the therapy, and the fact that outcome fundamentally depends on the underlying etiology, which differs in different studies (Neligan & Shorvon, 2010). Control of refractory and super-refractory status epilepticus was reported in 74% of the cases treated with anesthetics and variable rates of control were achieved with other therapies (Ferlisi & Shorvon, 2012).

The lack of evidence and the lack of outcome data in this situation require urgent remediation. Randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches discussed earlier. For this reason we have proposed a multinational database of therapies used in refractory and super-refractory cases and their outcomes. Only with such a database can evidence of effectiveness be gathered and progress made in this uncommon but difficult clinical situation.

Intensivists and neurologists from around the world are being asked to take part in a multinational audit in order that we may better understand the range of therapies, relative frequency of their usage, and outcome as well as information about the etiology of refractory status epilepticus. This is a prospective multicenter case audit using “active surveillance,” run by a Steering Committee comprised of neurologists and neurointensivists from around the world.

The aim is to collect information on the treatment of 1,000 cases over 12 months. Because it is an audit of physician's practice, with no intervention and no collection of protected health information, in most countries there is no need for ethics approval or patient consent. The audit will not have access to patient names or any other identifiable information. Physicians who agree to participate are asked to prospectively complete the online audit form for all patients they treat with the stage of refractory or super-refractory status epilepticus.

Every month, each participant will be sent a standard e-mail, asking if a case has been seen in the previous month. If they have, they will be sent an online form that should take less than 5 min to complete. After a case is reported, biweekly questionnaires are sent (taking 1–3 min to complete), until the physician indicates that the patient is no longer in the intensive care unit (ICU), at which time an outcome questionnaire is sent. Recorded information includes basic demographic information, history of epilepsy, type, etiology and duration of status epilepticus, choice, order and duration of antiepileptic and anesthetic therapy, use of nonpharmacologic therapies, duration of ICU stay, whether active therapy was withdrawn, outcome on discontinuation of anesthesia, and modified Rankin scale at 6 months.

As with any registry, the validity of this audit will depend on the range of participation. Therefore, we have enlisted a Steering Committee of physicians from around the world in order that we may capture the wide range of treatment practices used in refractory status epilepticus as well as information on outcomes. To participate, please register your interest at https://www.status-epilepticus.net/.

This exercise will form the basis for the formulation of clinical guidelines and point to areas of future research.

Disclosure

  1. Top of page
  2. Summary
  3. Disclosure
  4. References

The authors have no conflicts of interest.

The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Disclosure
  4. References