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Pathogenic mutations in DEPDC5 are responsible for a broad range of focal lesional and non-lesional epilepsies. Drug resistance and normal structural neuroimaging findings are common in more than half of patients. Neuromodulation techniques like vagus nerve stimulation (VNS) might be particularly attractive for those patients who are less likely to have a good outcome from surgical resection due to normal neuroimaging or whose epileptogenic zone involves eloquent regions, which if disrupted by resection could leave new deficits.