Does Treatment Aggressiveness Affect the Prognosis of Refractory Status Epilepticus?

By Jenna Martin
Special to EpilepsyUSA
Posted: August 3, 2006

Status epilepticus is a medical emergency that requires rapid and aggressive treatment to prevent neuronal damage, systemic complications and death. When the seizures associated with status epilepticus do not respond to initial drug therapy, thus becoming what is known as refractory status epilepticus, clinicians are encouraged to take very aggressive treatment measures, including coma induction and EEG suppression.

But how does treatment aggressiveness affect the prognosis of refractory status epilepticus? This is the question three physicians addressed in their latest study. Edward Bromfield, M.D, of Brigham & Women's Hospital, Andrea Rossetti, M.D., of the Swiss National Science Foundation, and Giancarlo Logroscino, M.D., PhD, of the Harvard School of Public Health presented their findings at the 59 th annual meeting of the American Epilepsy Society in Washington, D.C.

According to the researchers, there have been few studies closely examining the treatment of refractory status epilepticus, 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," said Bromfield, a member of the Epilepsy Foundation's professional advisory board.

Why is coma induction used as a treatment for refractory status epilepticus?

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 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," Rossetti said. "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."

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 percent of the cases, one coma-inducing antiepileptic drug was prescribed, whereas two or more were used in 55 percent 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 were more likely to lack a history of epilepsy or of status epilepticus prior to the study period than those whose status epilepticus was easily controlled," Bromfield said. "This probably reflects the fact that status epilepticus 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 refractory status epilepticus than less serious ones, such as drug or alcohol withdrawal. Furthermore, patients with refractory status epilepticus had a higher prevalence of nonconvulsive status epilepticus with coma, a form of status epilepticus that is 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 refractory status epilepticus has a lot to do with the underlying cause," Bromfield said. "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 refractory status epilepticus. The point is to stop the seizure, not necessarily to suppress the brain, which may lead to longer intensive care unit stays and more medical complications."

Both physicians further encouraged clinicians treating patients with refractory status epilepticus 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 refractory status epilepticus.

"These are the most widely used medications for coma induction," Bromfield said, "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."