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Patients with treatment-resistant epilepsy often cycle through multiple medications as they seek relief from the seizures that disrupt their lives. Yet in many cases, these drugs offer little benefit, reinforcing the long-held belief among experts that treatment-resistant epilepsy is a condition that remains stable at best—or gradually worsens over time.

A new study, however, challenges this longstanding notion by showing that a subset of these hard-to-treat patients do experience seizure relief, though researchers aren’t exactly sure what’s driving the improvement.

The study, published in JAMA Neurology, was part of the Human Epilepsy Project, a large, U.S.-based, observational study of patients with focal treatment-resistant epilepsy (FTRE) involving researchers from multiple institutions, including Yale neurologist Hamada Hamid Altalib.

For the study, researchers wanted to take a fresh look at whether seizure frequency in FTRE improves over time, and if so, why.

“The conventional wisdom is that once you’ve failed two medications, the likelihood of the third medication, or the fourth, making a patient seizure-free is less than 5%,” said Altalib, a professor of neurology at Yale School of Medicine. “But we showed that there are some people who do improve somewhat over time, even after three, four, or five medications, which was surprising.

“There was even a small group—about 17% of people—who were seizure-free for three months, which is a big deal because it challenges the current understanding and shows that people can improve,” he said.

Were new or ongoing treatments responsible for the improvement, or does seizure frequency simply wane over time? Researchers are still analyzing the data.

“The ‘why’ is of course the multi-million-dollar question that we can’t answer yet,” Altalib said. “But the fact that we showed real improvement is a big deal. It shakes up the whole field.”

Globally, the prevalence of epilepsy ranges between 0.6%-1.4% across respective populations, according to Altalib. The good news is that many people—40% to 60% of patients—become seizure-free when they begin anti-seizure medication, research shows. Another 30% have the medically refractory type that doesn’t respond to medication.

The Human Epilepsy Project is a long-term study with three parts. The new paper focuses on the second phase, during which researchers followed 146 patient volunteers, ages 16 to 65, from 10 epilepsy centers across the U.S. from May 2018 to September 2021. All participants had focal epilepsy and had tried at least four antiseizure drugs that failed to fully control seizures. Data collected included seizure frequency, medication use, device use, brain imaging, surgeries, monthly check-ins, medical record review, and case report forms.

“The nice thing about this study is that it’s a large epidemiologic study with a lot of biomarkers, genetics, and neuroimaging collected,” Altalib said.

Researchers analyzed the extensive data gathered, with Yale’s Biomedical Informatics and Data Science department coordinating information from both the first and second phases of the study.

“We’ve played a major role in data governance and managing this very complex data,” Altalib said. “We leveraged our informatics experts and other expertise. A lot of Yale faculty and staff helped make this happen.”

Researchers compared each person’s seizure frequency during the first and second halves of the study to determine whether seizures became less frequent over time. They found that most people, about 68%, experienced fewer seizures in the latter part of the study compared with the beginning. Another 13% were seizure-free for at least three months; 8% experienced no seizures for six months; and 3% for a year or longer.

Medication changes and the use of interventions, such as brain stimulation, varied among patients and yielded mixed results, with no one treatment strongly outperforming others. While many interventions exist, it remains unclear whether they change the long-term course of epilepsy or if patients simply improve over time with ongoing care, the researchers say.

But a key takeaway from the study is the importance of including a control group (a patient cohort that isn’t receiving any medication or intervention) when assessing whether a specific treatment is effective, Altalib said. Open-label studies (those without a control group) should not assume that treatment alone causes improvement, because some people experience an improvement without any intervention.

“What this work really underscores is the importance of continuous medical management and more rigorous, controlled studies to understand what really drives improvement,” Altalib said. “At the end of the day, we want to improve people’s quality of life. That’s why we’re in health care.”

More information: Ojas Potnis et al, Seizure Frequency Trends Over Time in Treatment-Resistant Focal Epilepsy, JAMA Neurology (2025). DOI: 10.1001/jamaneurol.2025.4085

Citation: Long-term study challenges assumptions about epilepsy recovery (2025, November 2) retrieved 2 November 2025 from https://medicalxpress.com/news/2025-10-term-assumptions-epilepsy-recovery.html

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