The unified myoclonus rating scale (UMRS) has been utilized to assess the severity of myoclonus and the efficacy of antiepileptic drug (AED) treatment in patients with Unverricht-Lundborg disease (ULD). Electroencephalographic (EEG) recordings are normally used as a supplemental tool for the diagnosis of epilepsy disorders. In this study, mutual information and nonlinear interdependence measures were applied to the EEG recordings in an attempt to identify the effect of treatment on the coupling strength and directionality of mutual information and nonlinear interdependences between different brain cortical regions. Two 1-h EEG recordings were acquired from four ULD subjects; one prior and one after a minimum of 2 months treatment with an add-on AED. Subjects in this study were siblings of same parents and suffered from ULD for approximately 37 years. Our results indicated that the coupling strength was low between different brain cortical regions in the patients with disease of less severity. Adjunctive AED treatment was associated with significant decrease of the coupling strength in all subjects. The mutual information between different brain cortical regions was also reduced after treatment. These findings could provide a new insight for developing a novel surrogate outcome measure for patients with epilepsy when clinical tools or observations could potentially fail to detect a significant difference.