Clinical trials in status epilepticus—The clinical perspective

Authors


Address correspondence to Reetta Kälviäinen, MD, PhD, Neurologist, Director, Kuopio Epilepsy Center, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland. E-mail: reetta.kalviainen@kuh.fi

Considering that status epilepticus (SE) is relatively frequent in neurologic practice, it is surprising that there are only a few randomized controlled studies (RCTs) on drug interventions reported (Prasad et al., 2005). For SE, observational studies seem to be easier to undertake, as carrying out RCTs in the emergency situation is problematic. The need for medical research programs involving patients with SE is real and profound. Only in well-performed clinical trials can hypotheses of clinical efficacy and safety be tested. However, involving this patient category in interventional trials raises ethical, juridical, and practical concerns. Clinical trials in patients with SE in emergency and critical care settings frequently involve patients with loss of decision-making capacity and, given the emergency nature of SE, facing very short therapeutic time frames.

In planning a trial it is essential to define clearly the SE phenotype to be studied. The response to treatment is greatly influenced by the duration of the SE before enrollment, response to previous therapy, SE type, etiology, and comorbidities. There is a relationship between ethnicity, socioeconomic status, and the incidence of SE. Outcome is influenced by the age of the patient. Therefore, studies should ideally be stratified to deal with these potential confounders (Neville et al., 2007). However, this means large sample sizes. On the other hand, accurate data about these prognostic factors are not always available at the time of enrollment, and excessively restrictive inclusion criteria or too broad exclusion criteria may limit the enrollment too extensively.

Informed consent in SE research can—given the emergency nature and severity of the condition, or due to pharmacologic sedation—seldom be obtained from patients themselves. Delaying the treatment to obtain informed patient or proxy consent might jeopardize both the life of the patient and the results of the trial. Several solutions are in use for obtaining consent in emergency situations. Proxies (legal representatives) or an independent physician can give consent before inclusion in research, or (patient or proxy) consent can be deferred for some time, or consent can even be waived (Jansen et al., 2009). The problems in getting the consent from a proxy include that proxies are not always available in the first moments of hospital or intensive care admission, or they are too overwhelmed to understand the provided information to give valid consent. Because of the problems in obtaining consent, patients included are often not representative of the typical SE population, and results of the trials, therefore, have low external validity.

It is no longer possible to treat SE with placebo. Therefore, although the RCT is always considered to be the gold standard, there are many limitations in the context of SE trials. Active comparator trials are possible, but true blinding is often also difficult or sometimes impossible. In addition, the most important question is not related to drug efficacy, but rather to strategies for the management of SE and generating guidelines that can be widely incorporated into clinical practice.

Good outcome after SE usually means cessation of seizures within a certain time period after the drug administration, absence of seizure recurrence within the next 24 h, and return to baseline neurologic function. The control of seizures can mean only clinical control or both clinical and electrographic control of SE. Secondary outcome measures include clinical outcome with a functional scale, incidence of focal neurologic deficits, incidence of epilepsy, incidence of cognitive decline, response by initial electroencephalography (EEG) findings, 30-day mortality, need for intensive care unit (ICU) treatment, time of ventilator treatment in patients treated in the ICU, incidence of thromboembolism, incidence of infectious complications requiring specific treatment, incidence of hypotension requiring specific treatment, and incidence of propofol infusion syndrome or other specific complications/adverse effects. It is also extremely important to follow carefully the vital signs and electrocardiography (ECG) as well as laboratory values when testing a new molecule.

There are several areas requiring attention in future research in SE. A universally acceptable definition of premonitory, early, established, and refractory status needs to be agreed upon and used consistently by investigators. Agreement on the definition of outcomes and method of data presentation is also desirable to facilitate meta-analysis. Successful treatment of SE requires multiple disciplinary involvement: emergency medicine, neurology, pediatrics, neurosurgery, radiology, and traumatology, and all of these disciplines should be involved also in the clinical research of of SE.

Acknowledgment

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

Disclosure: Dr. Kälviäinen has served on scientific advisory boards for UCB Pharma and Johnson & Johnson; has received funding for travel from UCB Pharma, Eisai, and Schwarz Pharma; serves as an editorial board member of Epileptic Disorders; has received speaker honoraria from UCB Pharma, Eisai, Orion, Schering-Plough, Janssen Cilag, and Pfizer; and has received research support from UCB Pharma, through the Academy of Finland and from the Vaajasalo Foundation.

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