Safety and adverse event profiles in neuromodulation therapies for drug-resistant epilepsy

Drug-resistant epilepsy (DRE) is associated with clinical and psychosocial burdens, and non-pharmacological therapies play an important role when seizure control cannot be achieved with antiseizure medications alone. Neuromodulation therapies, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have become important options for patients who are not suitable candidates for resective or disconnective surgery. Although these modalities have demonstrated efficacy for seizure reduction, they differ in surgical invasiveness, stimulation targets, device structures, programming strategies, and long-term management requirements. These differences result in distinct adverse event (AE) profiles for treatment selection. In this review, we summarize AEs and long-term management considerations associated with VNS, DBS, and RNS and classify them into four categories: procedure-related AEs, stimulation-related AEs including neuropsychiatric and cognitive issues, device-related AEs, and long-term management considerations. VNS avoids intracranial surgery but is associated with stimulation-related laryngopharyngeal symptoms and generator and wire management. DBS allows direct modulation of deep brain networks but carries risks of intracranial lead implantation, targeting accuracy, and psychiatric or cognitive effects. RNS provides closed-loop stimulation and chronic intracranial electroencephalographic recording, but requires implantation of intracranial leads and a cranially implanted neurostimulator, localization of the epileptogenic network, and specialized long-term data review, programming, and device management. Across all three modalities, device-related infection, battery depletion or replacement, and ongoing device management are common safety concerns. Understanding these modality-specific AE profiles may help clinicians select candidates, counsel patients and families, and develop safe and sustainable long-term treatment strategies for DRE.