Early Withdrawal of AEDs Post Surgery Is Safe

Fran Lowry

September 17, 2012

September 17, 2012 — Early withdrawal of antiepileptic drugs (AEDs) after pediatric epilepsy surgery seems safe and does not affect long-term seizure outcome or cure, according to TimeToStop, a retrospective observational study.

Early withdrawal "might unmask incomplete surgical success sooner, identifying children who need continuous drug treatment and preventing unnecessary continuation of AEDs in others," write Kim Boshuisen, MD, from University Medical Center Utrecht, the Netherlands, and colleagues of the TimeToStop study group.

The study was published online in Lancet Neurology.

Conclusions from previous studies on postoperative drug withdrawal in children have been conflicting. The purpose of the TimeToStop study was to assess the relation between timing of AED withdrawal and subsequent seizure recurrence, as well as long-term seizure outcome.

The study included 766 patients and was done in collaboration with 15 European pediatric epilepsy surgery centers. The patients were operated on between January 1, 2000, and October 1, 2008. All were younger than 18 years at the time of their surgery, had at least 1 year of postoperative follow-up, and had their AEDs withdrawn following surgery after reaching seizure freedom.

The researchers noted the interval from surgery to the start of AED reduction and the interval from surgery to the time of complete discontinuation, as well as the number of seizures that occurred during or after AED withdrawal, seizure freedom for at least 1 year, and cure, which was defined as being seizure free and off AEDs for at least 1 year, at the latest follow-up.

They found that the median time to the start of AED reduction after surgery was 12.5 months (95% confidence interval [CI], 11.9 - 13.2) and that 62 patients had a seizure recurrence during AED withdrawal.

More than one half (444 patients, 58%) were able to completely discontinue taking their AEDs. The median time to complete discontinuation was 28.8 months (95% CI, 27.4 - 30.2).

After complete AED discontinuation, 34 patients had a seizure recurrence. In all, 95 patients (12%) had a seizure recurrence.

The researchers also found that 26 of the 87 patients (30%) who restarted AEDs after a recurrence did not regain seizure freedom despite resuming their medication.

At the long-term follow-up, 629 children (82%) were seizure free for more than 1 year and had been followed for at least 1 year since the start of drug withdrawal, and 344 (45%) were cured.

Additionally, 32 children (4%) still had seizures (n = 26) or had not reached 1 year of seizure freedom (n = 6).

Multifocal lesions, confirmed by magnetic resonance imaging, and epileptic abnormalities on electroencephalography (EEG) decreased the chance of starting AED withdrawal, but a high number of AEDs used at the time of surgery, immediate postoperative seizure freedom, and no postoperative EEG abnormalities increased the chance of starting AED withdrawal, the authors report.

The fact that higher numbers of AEDs used at the time of surgery was associated with an increased probability of early withdrawal suggests that clinicians were less concerned about the risk for recurrence because of the protective effect of the remaining AEDs or else "were keen to reduce the high drug load," the authors write.

Other factors that increased the chance of achieving complete withdrawal of AEDs included tumors, Rasmussen's encephalitis, hemispherectomy, and not determining the completeness of the resection of the anatomical lesion.

Completeness of resection "is difficult to judge in daily practice and might therefore not have influenced AED withdrawal policy," the authors write. "An alternative explanation is that awareness of this important outcome predictor is relatively recent, and many of the patients in our cohort started withdrawal before publication of these findings."

Factors that decreased the chance of achieving complete withdrawal of AEDs included a high number of AEDs used at surgery, previous surgery, and epileptic abnormalities on postoperative EEG.

Neither the interval from surgery to the start of AED reduction or the interval from surgery to complete AED discontinuation affected the chance of regaining seizure freedom after restart of drugs or of reaching seizure freedom or cure for at least 1 year at final follow-up.

The study has several limitations, the authors point out. It included only patients for whom AEDs were withdrawn after they reached postoperative seizure freedom. Because surgical success was anticipated in this selected subgroup, the study results cannot be extrapolated to all children who undergo epilepsy surgery, they write.

They also point out that the timing of withdrawal depends to a large extent on subjective factors, such as the individual preference of the treating physician and request of the patient to stop, and these factors were not documented.

Finally, because the study included only patients who had achieved postoperative seizure freedom and for whom AEDs had been withdrawn, the predictors of seizure outcome identified in the study can be applied only to children in whom AEDs are tapered postoperatively, they write.

"The findings of this study justify the undertaking of a future randomised controlled trial to study the possible benefits and confirm the safety of early AED withdrawal after epilepsy surgery in children," they conclude.

In an accompanying comment, Dieter Schmidt, MD, of the Epilepsy Research Group, Berlin, Germany, agrees that such a study is needed.

Dr. Schmidt writes: "So, should we withdraw AEDs early in every child who is seizure free after surgery? The answer is probably yes, because, on the basis of the findings of Boshuisen and colleagues, even children at high risk of unfavourable outcome (including those who underwent hemispherectomy and incomplete surgery) do not seem to benefit from longer AED treatment."

He comments that the study has provided "clinically important insights and the authors are to be commended."

Finally, Dr. Schmidt concludes, "to move forward we need a randomised controlled trial of early versus no withdrawal of AEDs after surgery that establishes whether early withdrawal has advantages, such as cognitive improvement, and not just that it does not negatively affect seizure outcome."

The study was funded by the Dutch National Epilepsy Fund. Dr. Boshuisen has disclosed no relevant financial relationships. Dr. Schmidt reports financial relationships with Novartis, ViroPharma, and Biotie Therapies.

Lancet Neurol. Published online. Abstract, Comment