Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults

Abstract

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of ASM withdrawal were focal non motor-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients.

The pharmacological treatment of epilepsy in adults

“…T A B L E 7 Predictors of seizure recurrence post-ASM withdrawal after epilepsy surgery. [95][96][97] • History of focal to bilateral tonic-clonic seizures.…”

“…In adults who become seizure‐free after epilepsy surgery, ASM withdrawal may be attempted as early as 1–2 years post‐surgery as more than 75% of seizure recurrences occur within the first 12 months after epilepsy surgery 94 . Although the optimal timing for ASM withdrawal after epilepsy surgery is unknown, an individualized decision incorporating the other risk factors for seizure recurrence (Table 7) is required 95–97 . After epilepsy surgery, the ASM burden may be reduced by withdrawing ≥1 ASMs, but patients often remain on at least one ASM.…”

“…94 Although the optimal timing for ASM withdrawal after epilepsy surgery is unknown, an individualized decision incorporating the other risk factors for seizure recurrence (Table 7) is required. [95][96][97] After epilepsy surgery, the ASM burden may be reduced by withdrawing ≥1 ASMs, but patients often remain on at least one ASM.…”

Antiseizure medication withdrawal risk estimation and recommendations: A survey of American Academy of Neurology and EpiCARE members

“…For surgical vignettes, we similarly obtained clinician predictions and withdrawal recommendations. However, while a surgical postwithdrawal online risk calculator has very recently been validated (Ferreira‐Atuesta and colleagues 16 ; https://predictepilepsy.github.io/), its validation was not yet complete at the time of this survey. Thus, we incorporated surgical calculated predictions into our analysis but not the actual survey.…”

“…Physicians often overestimate treatment benefits and underestimate harms, and risk calculators tend to outperform humans at estimating risk 13 . Individualized postwithdrawal seizure risk calculators exist for medical 14,15 and surgical 16 patients. Yet, the degree to which clinicians' intuitive estimate of postwithdrawal seizure risk (“clinician predictions”) align with model (“calculated”) predictions remains unclear, which may inform when viewing calculated results might most useful.…”