The timing of antiseizure medication (ASM) withdrawal following resective epilepsy surgery was associated with early seizure relapse risk but not long-term seizure outcomes, a new multicenter study found.

In a large international cohort study of adults who achieved seizure freedom following epilepsy surgery, investigators found that tapering ASMs within the first 2 years of surgery nearly doubled the risk for relapse compared with later withdrawal.

Long-term outcomes, including complete medication discontinuation and ASM-free remission, were consistent regardless of ASM withdrawal timing, except for patients who stopped ASM use in the second postoperative year, who reported a modest reduction in seizure freedom.

“The higher immediate seizure relapse risk among people initiating ASM withdrawal earlier likely reflects a shorter ‘proof’ of surgical success,” lead investigator Carolina Ferreira Atuesta, MD, MSc, scientific researcher and clinical manager, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, and colleagues wrote. “Those who take longer to start withdrawal accrue additional seizure-free time, explaining a lower short-term relapse risk.”

The study was published online on January 28 in Neurology.

Balancing Postsurgery Risks

More than half of adults who undergo resective epilepsy surgery achieve seizure freedom and consider discontinuing ASMs to improve quality of life and reduce healthcare costs. The withdrawal of ASMs, however, carries the potential for seizure recurrence. 

Previous studies have identified factors associated with post-withdrawal seizure relapse, including postoperative focal seizures, history of generalized tonic-clonic seizures, and shorter intervals between surgery and ASM tapering. Despite these findings, guidance on the optimal timing for withdrawal after surgery remains limited.

To learn more, investigators conducted a multicenter observational cohort study using data from 12 international tertiary epilepsy centers. They analyzed data from 964 adults (51% women; median age, 34 years) who underwent resective epilepsy surgery between 1990 and 2016 and were seizure-free before initiating ASM withdrawal. Patients were required to have at least 1 year of postoperative follow-up.

Exclusion criteria included failure to achieve seizure freedom before tapering, disconnective procedures, multiple brain surgeries, and less than 1 year of follow-up. ASM withdrawal was categorized by the year in which tapering began: first, second, third, fourth, fifth, or later postoperative year.

Propensity score matching was used to balance baseline characteristics between groups, and covariates included age at surgery, duration of epilepsy, number of ASMs, history of generalized tonic-clonic seizures, psychiatric comorbidities, resection side and type, and pathologic findings such as hippocampal sclerosis.

The primary outcome was time to seizure relapse following ASM withdrawal. Secondary outcomes included seizure freedom, complete ASM discontinuation, and ASM-free remission during the final year of follow-up. 

Tapering Timing Is Key

Overall, 46% of participants began ASM withdrawal in the first postoperative year, 26% in the second, 11% in the third, 6% in the fourth, 3% in the fifth, and 7% after the fifth year. Overall, 35% of patients experienced seizure relapses over a median follow-up of 6 years.

After propensity score matching, patients who stopped ASM use in the first postoperative year had a significantly higher relapse risk than those who stopped taking them later (HR, 1.4; P = .003). Medication withdrawal during the second postoperative year was also associated with an increased relapse risk (HR, 1.18; P < .001). 

There was no significant increase in seizure relapse risk among those who stopped ASMs during the third, fourth, or fifth year after surgery.

When patients who initiated withdrawal within the first 2 years were pooled, relapse risk remained elevated (HR, 2.2; P < .001). This association was consistent across subgroups, including extratemporal resections, hippocampal sclerosis, lesionectomy, and lobectomy.

Despite a higher short-term relapse risk with earlier withdrawal, long-term outcomes, such as seizure freedom, complete ASM discontinuation, and ASM-free remission, were comparable across groups.

‘Real-World Evidence’

The findings suggest extended seizure-free observation may be beneficial for some patients following ASM withdrawal, at least for the first 2 years after surgery. 

“Our findings offer real‑world evidence that may inform future evidence‑based withdrawal protocols and follow‑up strategies,” they wrote.

Investigators also emphasized that relapses after early ASM withdrawal can often be reversible with medication adjustments and that short-term recurrence does not always suggest a poor long-term prognosis.

And shared decision-making is essential, they added. 

“Deciding whether and when to withdraw ASMs is a shared process involving individuals, caregivers, and clinicians, balancing preferences, risk of injury, social factors (eg, driving, work, and supervision), and clinical judgment,” they wrote.

Limitations of the study included its observational design, clinician-determined withdrawal timing, variable follow-up across centers, and small numbers in some subgroups.

The study received no targeted funding. Ferreira Atuesta reported having no relevant disclosures.