Status epilepticus (SE) is a medical emergency that requires rapid and aggressive treatment to prevent neuronal damage, systemic complications and death. When the seizures associated with SE do not respond to initial drug therapy; thus becoming what is known as refractory status epilepticus (RSE), clinicians are encouraged to take very aggressive treatment measures, including: coma induction and EEG suppression. But how does treatment aggressiveness affect the prognosis of RSE? This is the question Edward Bromfield, M.D, Brigham & Women’s Hospital and Harvard Medical School, Andrea Rossetti, M.D., Swiss National Science Foundation, and Giancarlo Logroscino, M.D., PhD, Harvard School of Public Health, addressed in their latest research study. They presented their findings at the American Epilepsy Society 59th Annual meeting in Washington, DC.

According to the researchers, there have been few studies closely examining the treatment of RSE, particularly comparisons among drugs used for coma-induction. Furthermore, the impact on outcome of EEG suppression remains unclear. “With this study our aim was to determine whether outcome in refractory status was affected by the specific drug or drug combination used, or by the depth of coma as measured by degree of EEG suppression.”

Why is coma induction used as a treatment for RSE?

Coma Induction, as its name implies, is a treatment in which a temporary coma is deliberately induced (using drugs) to “rest the brain” in a variety of situations, including reducing swelling after head injury. While brain swelling can occur in status epilepticus, it does not usually lead to significant increases in pressure, and the purpose of induced coma here is more to make sure that seizures have stopped. It is not clear whether resting the brain provides any further benefit. “In the case of refractory status epilepticus, the seizure has no stopping mechanism. Unlike other types of seizures, which eventually stop on their own, these seizures do not and require drastic medical intervention such as coma induction to allow the brain to rest. By inducing a coma, we make it less likely that seizures will recur, at least during the period of intense treatment. EEG is the tool we use to determine the depth of the coma and make sure that seizures have stopped,” said Rossetti.

Results

The researchers identified cases that were refractory to first-line (benzodiazepines) and second-line (phenytoin, valproate, phenobarbital, or other) treatments, and needed intubation and induced coma for clinical management. The cases were collected from a retrospective database of two hospitals in Boston. In 45% of the cases, one coma-inducing AED was prescribed, whereas two or more were used in 55% of episodes. The most commonly used medications were pentobarbital, propofol and midazolam, all of which are sedative drugs that produce anesthesia if the doses are high enough. Barbituates showed a tendency to be used preferentially in episodes where the cause of status was more likely to be life-threatening.

“What we found was that patients with refractory status epilepticus (RSE) were more likely to lack a history of epilepsy or of status epilepticus (SE) prior to the study period than those whose SE was easily controlled. This probably reflects the fact that SE is really a symptom of other conditions, and the more serious of these conditions, such as brain tumors, encephalitis, or major stroke, are more likely to lead to RSE than less serious ones, such as drug or alcohol withdrawal,” said Bromfield. Furthermore, patients with RSE had a higher prevalence of nonconvulsive SE with coma, form of SE that is itself associated with serious illness and poor outcome.

Implications of the Study

Bromfield and Rossetti both echo the same enthusiasm regarding the findings of their study.

“The outcome of RSE has a lot to do with the underlying cause. For example, we found that mortality appears to be independent of the specific drug or drugs used for coma induction and the extent of EEG suppression. Therefore, we believe that the underlying cause is the main determinant of outcome. Also, we want to emphasize to clinicians that there is no one right treatment of RSE. The point is to stop the seizure, not necessarily to suppress the brain, which may lead to longer ICU stays and more medical complications”, they said. They encourage clinicians treating patients with RSE to tailor their treatment interventions on a case-by-case basis, at least until studies show clearly that one treatment is superior, and believe that the most aggressive treatment may not necessarily be the most effective.

They are currently in the process of designing a prospective study exploring the effectiveness of propofol versus pentobarbital in RSE. “These are the most widely used medications for coma induction, and though retrospective studies such as this one have not been able to show differences, a prospective, randomized trial is the best way to answer this question,” said Bromfield.

The abstract of this study is published in Epilepsia 2005, Vol. 46, Supplement 8, p.338.