Established and emerging neuromodulation for drug-resistant epilepsy

Drug-resistant epilepsy concerns approximately 30% of epilepsy patients. Surgical interventions might not be an option, especially in case of generalized or multifocal seizures or if there is a high risk of neurological defects caused by the resection. Currently widely approved neuromodulation approaches consist of invasive methods: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS), all of which are related to a substantial seizure reduction efficacy, with responder rates around 40%. Side effects, mainly related to infection and local complications, are relatively infrequent, but still nonnegligible, inducing treatment failures and higher costs. Newer, emerging technologies are starting to offer more focal or less invasive alternatives. Focal cortical stimulation (FCS), which is regionally approved in Europe, involves the implantation of an epicranial electrode, while trigeminal nerve stimulation (TNS), transcranial magnetic stimulation (TMS) and focused ultrasound (FUS) do not breach the skin. In the case of FUS, even deep brain structures can be targeted without influencing the more superficial cortex. While these techniques have been studied less intensively than the above established methods, preliminary studies suggest potential seizure reduction in selected cohorts, but evidence remains limited and less mature than for established invasive modalities. This narrative review aims to provide a comprehensive comparison of established and newer techniques for neuromodulation in drug-resistant epilepsy, focusing on their mechanisms of action, clinical indication, efficacy, safety profile and limitations, in order to provide the best treatment strategies tailored to the individual patient.