Genetic speed has improved our understanding of epilepsy, but its clinical application is still in its infancy, with epileptic encephalopathy as its main target. “The Epi4K and Epilepsy Phenome/Genome Project performed whole-exome sequencing of 264 patients with epileptic encephalopathy (149 with infantile spasms and 115 with Lennox-Gastaut syndrome) and their parents. The investigation identified 329 patients with de novo mutations, 72% of which were missense and 7.5% presumed loss-of-function. Four patients had de novo mutations in GABRB3 and two patients had mutations in ALG13; these mutations showed a clear association with epileptic encephalopathy. Genes with de novo mutations in this cohort also included CACNA1A,CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR, and NEDD4L. protein network connectivity maps showed that de novo mutations in this cohort clustered on specific gene clusters, including fragile X chromosome protein-regulated genes. This study identified novel genes and confirmed significant genetic heterogeneity in infantile spasms and Lennox-Gastaut syndrome. Importantly, the study aims to provide information on the phenome range of specific gene mutations in epileptic encephalopathies, which is important to identify abnormalities in the genes of interest in patient subjects. Large-scale dynamic analysis at the circuit level is critical for understanding how disruptions at the molecular or cellular level in normal animals can produce epilepsy, and Paz and colleagues show that in a rat model of post-stroke epilepsy, increased input membrane resistance and altered expression of hyperpolarization-activated cyclic nucleotide-gated ion channels cause specific thalamic neurons directly connected to damaged somatosensory cortex to exhibit abnormal excitation . This study provides compelling evidence that structures distant from the primary damaged tissue are connected via remote prominences and can be involved in abnormal brain activity, such as epilepsy. The findings emphasize the importance of epileptic networks and provide supportive evidence for neuromodulation in the treatment of refractory epilepsy. The development of translational research continued into 2013. Overexpression of the multidrug transporter P-glycoprotein in the brains of epileptic patients was proposed as a major mechanism of drug resistance. However, its clinical relevance has been questioned, mainly because direct visualization of P-glycoprotein expression in patients with drug-resistant epilepsy is very difficult.Feldman and his colleagues used (R)-[11C]verapamil in a PET study to provide the first in-human evidence that P-glycoprotein overexpression is associated with drug resistance in patients with temporal lobe epilepsy (TLE). Whether the relationship between drug resistance and P-glycoprotein overexpression is causal is unclear, but this study has provided a fundamental approach for future translational studies of drug resistance in patients with epilepsy. The mammalian target of rapamycin protein (mTOR) is part of a large-scale signaling pathway in the pathogenesis of compound tuberous sclerosis (TSC) and an important target for epilepsy therapy in acquired epilepsy. kreuger and his colleagues conducted a prospective, multicenter, open-label, everolimus 2/3 clinical trial in 20 patients with refractory epilepsy due to TSC. phase 2/3 clinical trial. This study provides the first convincing study of the role of an mTOR inhibitor in controlling seizures in patients with TSC and will pave the way for future large-scale clinical trials. In addition to TSC and its associated genetic epilepsy, clinical applications of mTOR inhibitors are expected to go much further, including various acquired epilepsy syndromes. Patients with epilepsy have a higher premature mortality rate than the general population, at least partially attributable to direct death from epilepsy and its potential causes of death. However, results from a long-term follow-up population study from Sweden suggest that psychiatric comorbidities account for a large proportion of this mortality. The premature mortality rate in patients with epilepsy was 8.8%, much higher than in the general population (0.7%; adjusted ratio [aOR] of 11.1). External causes accounted for 15.8% of premature mortality, with non-traffic accidents (aOR 5.5) and suicide (aOR 3.7) having a higher proportion. Co-morbidity of psychiatric disorders in 75.2% of those who died from external causes was strongly associated with individuals suffering from depression (aOR 13.0) and substance misuse (aOR 22.4). This study highlights the significant impact of co-occurring psychiatric disorders on premature death in patients with epilepsy as a manageable factor that could be targeted to prevent premature death in these patients. Psychiatric disorders have been identified as a significant risk factor for medically intractable and poor quality of life in patients with epilepsy, and their detrimental factors now extend to premature death. The association between the high incidence of substance misuse (11.5%) and high risk of premature death in patients with epilepsy compared to the general population (2.9%) is a very important finding and needs further investigation. Epilepsy research in 2013 was characterized by the use of new technologies and well-designed experimental models, which further pushed us closer to goal-oriented concepts in trials and clinical investigations. We hope to see further breakthrough treatments for refractory epilepsy in the coming years.