Valproate Switch Associated With Poor Seizure Control in Women With Idiopathic Epilepsy

Carlo Di Bonaventura, MD, Department of Human Neurosciences, University di Roma Sapienza

Carlo Di Bonaventura, MD

Study results suggest that women aged 13 to 50 years with idiopathic generalized epilepsy who switched off of or avoided valproate were more likely to have unsatisfactory seizure control.¹

Notably, with the study population (n = 198) being of childbearing age, the group of investigators, including Carlo Di Bonaventura, MD, Department of Human Neurosciences, University di Roma Sapienza, assessed the outcomes of those switching their medication in consideration of pregnancy (n = 28). They observed clinical worsening post-switch in 71.4% (n = 20) of patients, with most experiencing seizure relapse within 2 months. In total, 39.3% (n = 11) switched back during follow-up.

“The treatment of female patients with IGE during reproductive age has always been challenging, especially after the restrictions of regulatory authorities on valproate use,” Di Bonaventura and colleagues wrote. “In this specific population, taking valproate at last medical observation was strongly associated with seizure remission.”

“Our findings further highlight the complexity of the therapeutic management of female patients of reproductive age,” they added.

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The retrospective multicenter study reviewed data from the nearly 200-patient group with a median follow-up of 11.01 years. Valproate was the first-line agent for 45.5% (n = 90) of the population, with 25.8% (n = 51) on levetiracetam, 10.1% (n = 20) on lamotrigine, 6.1% (n = 12) on phenobarbital, and the remaining 17 patients on ethosuximide topiramate, carbamazepine and clonazepam.

The overall seizure remission rate at last medical observation was 62.7%, which was significantly different between those taking and those not taking valproate at their last visit (78.8% vs 51.7%, respectively; P <.001). Taking the therapy at last medical observation was strongly associated with remission in both the general population (P <.001) and those with juvenile myoclonic epilepsy (n = 81; P <.001).

Of those 51 patients who switched off of valproate, 70.6% (n = 36) experienced a clinical worsening. Switching back to VPA was more frequently associated with seizure remission at last observation (P <.001).

In total, of the 90 patients who started on valproate, 33.3% (n = 30) remained on it, while 66.7% (n = 60) switched to another treatment. The most common reason for the switch was the planning of a pregnancy, which occurred in 31.1% of cases. Levetiracetam and lamotrigine were the most frequent alternatives (45.1% and 25.5%, respectively). Among the 108 patients taking first-line therapy other than valproate, 34 added it during follow-up due to poor seizure control. In total, only 15% (n = 9) of those on first-line valproate switched due to poor seizure control.

In the 28-patient cohort considering pregnancy, 82.1% (n = 23) of patients were taking valproate as monotherapy, with 85.7% (n = 24) being in remission from seizures and 14.2% (n = 4) were experiencing what were described as minor seizures. Monotherapy numbers dropped significantly after the switch, from 23 to 14 patients, equivalent to a 32.1% difference (P = .02).

Di Bonaventura and colleagues observed a statistically significant difference in overall seizure remission rates, dropping from 85.7% to 53.5% (n = 15; P = .01). Additionally, generalized tonic-clonic seizures occurred at a higher rate, with no patients experiencing them to 17.8% (n = 5) of patients after the switch (P = .05).

“This observation seems to provide additional information about the debated topic of valproate use in this specific population, highlighting the need for accurate counseling, which especially deals with the risk of seizure worsening and the potential increase of drug burden,” the authors detailed. “In light of these findings, clinicians should thoroughly discuss with their patients about potential risks and benefits of valproate avoidance, especially in cases of specific syndromic contexts.”

The findings, the group noted, are in line with the International League Against Epilepsy’s position on the banning of valproate in the childbearing population, especially in patients with “more insidious epileptic syndromes.”²

The study was not without limitations, as the group acknowledged, with its retrospective design, interpretation challenges due to varying follow-up duration, and selection bias all being cited as limiting factors.

“Overall, our data further highlight the need for alternative drugs that may ensure both effectiveness and safety in women of reproductive age with idiopathic generalized epilepsy,” they concluded. “However, prospective studies on larger populations are warranted to provide more solid evidence.”

REFERENCES

1. Irelli EC, Morano A, Cocchi E, et al. Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome. Epilepsia. 2019;61:1. doi: 10.1111/epi.16407.

2. Tomson T, Marson A, Boon P, et al. Valproate in the treatment of epilepsy in women and girls Pre-Publication Summary of Recommendations from a joint Task Force of ILAE-Commission on European Affairs and European Academy of Neurology (EAN). Position statement. Published 2015. ilae.org/files/dmfile/ValproateCommentILAE-0315.pdf. Accessed January 27, 2020.