Status epilepticus is an emergency wherein a patient is in a persistent state of seizures. If not stopped quickly, the seizures can cause life-altering damage.
“If a seizure doesn't end by itself, it becomes a life-threatening emergency," says Jaideep Kapur, MD, a neurologist and physician-scientist at UVA Health who specializes in epilepsy and seizure care. “When someone has a convulsive seizure that lasts more than 5 minutes, they can stop breathing. We discovered some time ago that if you wait, the seizures become tougher and tougher to treat.”
Benzodiazepines are the first-line treatment for stopping status epilepticus. "A lot of clinical studies show that you should give benzodiazepines, and you should give them early," says Kapur. Unfortunately, this intervention fails in about 1/3 of cases. But while several second-line treatments exist, "there's been no clear guidance" outlining the most effective therapy.
Three Second-Line Choices, But What’s Best?
While fosphenytoin is the FDA-recommended second-line treatment, it also doesn’t have a great response rate — only about 1/2 of patients respond.
Among the other drugs also used as second-line treatments, none had clear guidance on their optimal dosages, nor had studies that definitively demonstrated the most effective one to use. Additionally, the optimal second-line treatments and dosages weren’t yet established for children.
“There are two things you want to know when you're trying to save lives: One is that the drug should work. The second is it should be safe. And physicians particularly want to know, which is the safest drug to use in children?” To answer these questions, Kapur led a team of international researchers for a groundbreaking study. They found the optimal dosages for 3 second-line medications, and showed that all exhibited about the same effectiveness and safety in adults. But for children, one medication was associated with a significantly higher rate of intubation.
Setting Up for Success: ESETT
Kapur and his team conducted the Established Status Epilepticus Treatment Trial (ESETT), which examined the top three medications used in benzodiazepine-refractory established status epilepticus: fosphenytoin, valproic acid, and levetiracetam.
For this multicenter, randomized, double-blind, comparative effectiveness study, the ESETT researchers recruited 478 patients from 58 hospital emergency departments (including UVA Health) in the U.S. Eligible patients aged 2 years and older were treated for convulsive seizures that persisted after receiving benzodiazepine.
“A group of investigators met in Austria in 2010 and agreed we should do a clinical trial to find out what's the best route to choose for treatment. The group elected me to lead [the study],” says Kapur. “So my job was to lead the whole team until we got all the approvals and then keep the study going to get it finished.”
Getting ESETT set up and approved presented some unique challenges. “This trial had a very sophisticated trial design. We used a Bayesian adaptive design. The idea was to optimize the trial, in that if at specific points in the trial, we’re 97.5% certain that all three are equal, we'll stop because there is no point going on and enrolling more and more subjects. We ran millions of computer simulations that we shared with the FDA,” says Kapur.
“The process is long because we have to agree on the drugs studied, what dose we’ll test, and then make sure that the FDA agrees to this trial. Remember, these trials are done when the patients are unconscious — so these are done under special rules called 'Exception Form Informed Consent (EFIC)'. You do get consent later, but it's an extraordinary way of doing so. That's how you do research in life-threatening emergency situations,” explains Kapur.
Arriving at Clarity for Status Epilepticus Patients
During the study, the primary efficacy outcome was defined as the end of seizure activity and improved responsiveness within 60 minutes of receiving the study drug, without needing additional antiseizure medication. Ultimately, the three drugs exhibited about the same effectiveness and safety in adults.
“We compared all three, fosphenytoin, valproic acid, and levetiracetam, and we found them to be equally safe. They work in about half of the patients, and you should use the drug you're most comfortable with. Many neurologists are most comfortable with levetiracetam, and you can go ahead and use it. But make sure you use the right dose as we proposed in that trial,” cautions Kapur.
With children, effectiveness was about the same but with some differences in safety. “In children, I would say to notice that our data shows that fosphenytoin was associated with a higher rate of intubation. We could not find a specific reason why children who were treated with this drug had a higher rate of intubation than the other two drugs. But as you pick a drug, you should know that even though all three drugs work equally well, we found a three times higher rate of intubation in children treated with fosphenytoin,” says Kapur. See the study results.
More Research to Yield Better Outcomes in Status Epilepticus
While Kapur and the team are happy to get clarity around these medications, they know there is still more work to do to help patients. He explains: “The disappointing part is not that one drug was not better, the disappointing part is 50%. You still leave half the patients seizing, and that's unacceptable. I want to get as many treated as possible.”
The team is planning the next trial. "We’re looking at adding ketamine to levetiracetam to test it, which may improve the rate by about 15-20%. Same old computer simulations are going on and looking at everything. But it will be another year and a half or two before we get the first patient.”
A Center of Leadership in Epilepsy Science
UVA Health’s epilepsy team continuously strives to advance the state of care for their patients. According to Kapur, the team “has been internationally renowned since the mid-70s." The leadership roles taken on by the team members explain why: The founder of the program, Fritz Dreifuss, served as president of the American Epilepsy Society (AES) and the International League Against Epilepsy. Kapur has served as president of the AES and is now chair of the International League Against Epilepsy – North America board. His colleague, Nathan Fountain, MD, has been the president of the Epilepsy Foundation of America. UVA Health neurology chair Howard Goodkin, MD, PhD, serves on the board of directors of the AES. Edward Bertram, MD, serves on the executive committee of the International League Against Epilepsy. Additionally, the team at UVA Health boasts several NIH-funded investigators providing key research in the basic science of epilepsy.
For Kapur, serving as a physician and researcher among his colleagues at UVA Health is an honor. “So this is a major center for epilepsy research in the country. All of these leaders in epilepsy research are here, and many have been here. Many are nationally and internationally recognized leaders, and it's in that fertile environment from which I've grown. There were giants before me, and we really rest on their shoulders here.”