Background: Vagus Nerve Stimulation (VNS) is an efficacious neuromodulatory treatment for patients with drug resistant epilepsy (DRE). In many VNS treated patients, seizures are not fully controlled. These patients often represent a highly refractory group in whom novel anti-seizure medication (ASM) may be tried. This study evaluates the effectiveness of Cenobamate (CNB) in patients previously treated with VNS. Methods: The medication history of all patients treated with VNS at Ghent University Hospital and HUB-Hopital Erasme Brussels between 1995 and 2024 was reviewed. In patients who received an add-on treatment with CNB after at least 12 months of VNS therapy, mean monthly seizure frequency before VNS, after VNS, and after CNB was assessed. Results: 54/620 patients treated with VNS between March 1995 and November 2023 were treated with CNB after a median VNS treatment time of 9 years. With VNS, 13/52 (25%) had a seizure frequency reduction of ≥50%. Side-effects were mild and stimulation-related. After add-on of CNB (median daily dosage of 200mg) for a median follow-up of 10 months, 24/54 (44.4%) became responders. Of these patients, 6 (11.1% from total cohort) reported seizure freedom for a median duration of 26 weeks. Almost half (46.2%) of the VNS non-responders became CNB responder. The median number of concomitant ASM was 3. In 20/54 (37%), the number of ASM was reduced. 7/54 (13%) stopped CNB because of side-effects. Fatigue was the most prevalent side effect in 23/54 patients (42.6%). Conclusion: In DRE patients treated with VNS therapy who could benefit from further improvement in seizure control, add-on treatment with CNB is useful. This most recently marketed ASM leads to a significant improvement in seizure frequency in more than 40% of the patients.

Benjamin Legros has received speakers and board honoraria from LivaNova and Angelini Pharma. Alfred Meurs has received speakers fees from Angelini Pharma. Mathieu Sprengers has been supported by Angelini Pharma to attend European Epilepsy Congress 2024 (registration fee + travel costs). Ann Mertens has received speakers fees from Angelini Pharma and has been a consultant for LivaNova Belgium NV. Frank Dewaele is a consultant for Synergia Medical and has been a consultant for LivaNova. Paul Boon reports a relationship with LivaNova Belgium NV that includes: board membership and consulting or advisory. Paul Boon reports a relationship with Medtronic that includes: board membership and consulting or advisory. Paul Boon reports a relationship with Angelini Pharma Inc that includes: consulting or advisory. Paul Boon reports a relationship with Synergia Medical that includes: board membership. Kristl Vonck reports a relationship with LivaNova Belgium NV that includes: board membership, consulting or advisory, and speaking and lecture fees. Kristl Vonck also reports a relationship with Synergia Medical that includes: board membership and consulting or advisory. Kristl Vonck reports a relationship with Angelini Pharma Inc that includes: consulting or advisory and speaking and lecture fees. Kristl Vonck reports a relationship with IVEA care that includes: consultancy. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Lara Hogeveen is supported by the Bijzonder Onderzoeks Fonds (BOF) UGent, special research fund from Ghent Univeristy and supported by 4brain fund from Ghent University. Alfred Meurs is supported by 4brain fund from Ghent University. Veerle De Herdt is supported by grants of the FWO Flanders and 4brain fund from Ghent University. Mathieu Sprengers is supported by 4brain fund from Ghent University. Ann Mertens is supported by 4brain fund from Ghent University. Stefanie Gadeyne is supported by 4brain fund from Ghent University. Robrecht Raedt is supported by grants of the FWO (Fonds Wetenschappelijk Onderzoek) Flanders and Bijzonder Onderzoeks Fonds (BOF) UGent special research fund and 4brain fund from Ghent University. Paul Boon is supported by grants of the FWO Flanders, BOF UGent, Ghent University Hospital, and E-Epilepsy (European Union) and 4brain fund from Ghent University. Kristl Vonck is supported by the BOF UGent special research fund and 4brain fund from Ghent University.

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"Health, Innovation and Research Institute (HIRUZ)" and "Commissie voor Medische Ethiek (CME)" gave ethical approval for this work at Ghent University Hospital. "Comite d'ethique hospitalo-facultaire Erasme-ULB" gave ethical approval for this work at HUB Hopital Erasme Brussels.

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