30 years of vagus nerve stimulation trials in epilepsy: Do we need neuromodulation-specific trial designs?

Neuromodulation therapies represent an important treatment arm for patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery. Vagus nerve stimulation (VNS) - the neurostimulation modality in focus in this review - was the first available neuromodulatory therapy for DRE and was followed by anterior thalamic deep brain stimulation (ANT-DBS) and responsive neurostimulation (RNS). Although no comparative trials of these treatments have been performed, published data and clinical experience suggest comparable effectiveness. In VNS, DBS and RNS seizure reduction is delayed and increases over time raising the question of anti-epileptogenic mechanisms of neuromodulation. Considering the long-term effectiveness assumed for neuromodulatory treatments and the chronic nature of drug-resistant epilepsy, study designs allowing for long-term comparative observations would be of great value, but are hindered by the inherent nature of a long-term [surgical] control group and the bias associated with open-label trials. New trial designs using objective endpoints are needed, and may be aided by novel biomarkers of risk and disease severity for specific epilepsy populations.