In patients with focal epilepsy, the results of the SANAD II study once again confirmed LTG as the first-line agent. Previous data from pregnancy registries indicated at most only slightly increased teratogenicity in a dose-dependent manner when LTG was taken at a dose of > 325 mg/day at the time of conception. Although in routine clinical practice LEV is frequently prescribed for focal epilepsy, no doubt in part due to the option of faster dosing, LTG is probably still the more effective and cost-efficient form of treatment as the agent of first choice in men and women. It must also be noted here that the slow dose escalation required with LTG does not lead to an increased risk of seizures in this dose escalation phase compared to LEV. Thus, in the LaLiMo Trial, in which LTG and LEV were compared in the initial monotherapy of newly diagnosed focal and generalized epilepsy, no difference was seen between LTG and LEV with regard to seizure control in the first 6 weeks of treatment (= primary outcome parameter: [10]). Likewise in the SANAD II study, there was no difference in seizure control between LTG, LEV, and ZNS in the first weeks of treatment [8]. Thus, an initial bridging combination therapy with LEV and LTG cannot be recommended.

Lamotrigine has been confirmed as the first-line agent in focal epilepsy

Nevertheless, in clinical practice, LEV is increasingly used as the first-line medication for focal and generalized epilepsy. This choice is supported by the ILAE and the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF) guideline 030/041 of 2017. A recent prospective study conducted by the Epilepsy Center Hessen, Germany, on the clinical reality in the initial treatment of focal epilepsy, presented at the German-speaking Tri-Country Conference, showed that LEV is used in the majority of patients (64%). A statistical comparative analysis is currently not yet possible in the study, which has been ongoing since 2018 [3]. However, SANAD II also showed there was no longer a difference between LEV and LTG for 24-month remission in this treatment group. Since neither drug has yet shown increased teratogenicity or developmental delay in children with intrauterine exposure, the choice between LEV and LTG is not influenced by the sex of the patient.

Even more exciting are the implications of the SANAD II trial results in generalized epilepsy. There is certainly no doubt among experts that VPA is the most effective drug in generalized as well as in difficult-to-classify epilepsy. This was also the general consensus even before the publication of the SANAD II results. Nevertheless, in routine clinical practice, LEV is very often prescribed for women of childbearing age even for generalized or difficult-to-classify epilepsy.

However, once the results of the SANAD II study are available, one will certainly need to discuss more intensively whether and under what circumstances a woman of childbearing age can or may also be deprived of the most effective treatment method. At the very least, despite the teratogenicity of VPA as well as its negative effects on cognitive development and the increased risk for autism spectrum disorders in children exposed to the drug during pregnancy [1], treatment with VPA must be discussed with the patient, and the efficacy of the treatment must be weighed against the side effects and especially the negative effects in each individual case. This is certainly only possible if the patients themselves are sufficiently informed about all positive and negative aspects. After all, the therapeutic goal remains freedom from seizures, and one should not lose sight of this.

Having said that, a 2021 European expert opinion published on the use of VPA in girls and women of childbearing age was that seizure-associated risks during pregnancy must be weighed against the teratogenicity-associated risks of VPA, but that, in general, VPA should not be used as a first-line medication in girls older than 10 years and women [11]. Also, the demonstrated increased teratogenicity due to VPA and its negative impact on the cognitive development of the unborn child have led the European Medicines Agency (EMA) to make a strong recommendation (EMA, 21 Nov 2014) to limit the use of VPA to cases where it is essential. In evaluating the various pregnancy registries, it appears that dosages above 650 mg/day should not be sought when VPA is essential. The form filled in annually by the specialist physician confirming that the patient has been provided with the information on risks should be completed.

The problem of the individual counseling situation has now become even more acute. It is not so easy to refuse patients—as is often the case—the most effective treatment virtually apodictically from the outset. As justiciable as teratogenic effects of VPA may rightly be if patients are uninformed of the risks, it is now quite conceivable with the availability of the SANAD II study that forensically relevant questions could be raised in the case of serious consequences of an obviously second-best epilepsy treatment (regardless of whether with LTG or LEV) that has omitted the use of VPA.

In men, on the other hand, the decision is much easier, since VPA is the drug of first choice for generalized and difficult-to-classify epilepsy. There are currently no known negative effects on a child conceived by a man receiving VPA treatment.

Valproate is the first-choice drug for men with generalized and difficult-to-classify epilepsy

However, in December 2022, the public health authorities in the United Kingdom, citing studies on the adverse effect of VPA on testicular size and sperm motility, also restricted the use of VPA in men under 55 years of age: The UK’s Commission on Human Medicines (CHM) recommends that no patient under the age of 55 years should be placed on VPA unless two specialists independently conclude that there is no other effective or tolerated treatment in the individual case [13].

At the recent Epilepsy Congress in Berlin, Germany, in March 2023, the new guidelines for the treatment of first seizures and adult-onset epilepsy were presented for the first time in a lecture, incorporating the results of the SANAD II study [5]. In summary, the gender-specific recommendations within these new guidelines are as follows.