Although the past 30 years have stirred up a whirlwind of neurological research that has dramatically expanded therapeutic options for patients with epilepsy, historical pioneers in the field might be disappointed at the fact that treatment response has remained stubbornly stagnant. “Plus ça change, plus c’est la même chose,” they might say: The more things change, the more they stay the same. In fact, since 1993, , with roughly two-thirds of patients achieving seizure freedom and a third still struggling with treatment resistance.
Dr. Jacqueline A. French
But if you widen the lens and look towards the horizon, things are “on the cusp and going like a rocket,” said Jacqueline A. French, MD, professor of neurology in the Comprehensive Epilepsy Center at NYU Langone Health, New York. While treatment response rates may be stuck, adverse effects of those treatments have plummeted, and even treatment-resistant patients dealing with residual seizures live a much freer life with far fewer and less serious episodes.
Simpler times
In the late 1980s, just as Dr. French was finishing her second epilepsy fellowship at Yale, it was “almost laughable that things were so simple,” she recalls. “There were a few major centers that were doing epilepsy surgery … and in the world of medication, there were just five major drugs: phenobarbital, primidone, carbamazepine, phenytoin, and valproate.” That all changed as she was settling in to her first academic position at the University of Pennsylvania, with the “explosive” introduction of felbamate, a new antiseizure drug whose precipitous rise and fall from favor cast a sobering shadow which set the course for future drug development in the field.
“The felbamate story has a lot to do with what came after, but it was a drug that was much more advantageous in regards to a lot of the things that we didn’t like about antiseizure medicines or antiepileptic drugs as we called them at that time,” she said. The older drugs affected the cerebellum, making people sleepy and unable to concentrate. They also came with the risk of serious adverse effects such as hepatic enzyme induction and teratogenicity. Not only was felbamate nonsedating, “it actually was a little bit alerting,” said Dr. French. “People felt so different and so great on it, and it was effective for some seizure types that we didn’t really have good drugs for.” Very quickly, felbamate became a first-line therapy. Within its first year on the market, 150,000 newly diagnosed patients were started on it, “which is unthinkable now,” she said.
Sure enough, it all came crashing down a year later, on Aug. 1, 1994, when the drug was urgently withdrawn by the U.S. Food and Drug Administration after being linked to the development of aplastic anemia. “There was a day that anybody who was there at the time will remember when we all got the news, that everybody had to be taken off the drug,” Dr. French recalled. “We spent the weekend in the chart room, looking chart by chart by chart, for who was on felbamate.”
Until then, Dr. French had been straddling the line between her interests in pharmacologic versus surgical treatments for epilepsy. In fact, during her second epilepsy fellowship, which was dedicated to surgery, she published “Characteristics of medial temporal lobe epilepsy” in Annals of Neurology, one of the most-cited papers of her career. “Epilepsy from the temporal lobe is the biggest and best shot on goal when you’re talking about sending somebody to epilepsy surgery and rendering them completely seizure free,” she said. “Early in my career at the University of Pennsylvania, it was all about identifying those patients. And you know, there is nothing more gratifying than taking somebody whose life has been devastated by frequent seizures, who is injuring themselves and not able to be independent, and doing a surgery, which is very safe, and then all the seizures are gone – which is probably why I was so excited by surgery at the time.”
For a while, in the early 1990s, temporal lobectomy eclipsed many of the other avenues in epilepsy treatment, but it too has given way to a much wider variety of more complex techniques, which may be less curative but more palliative.
