Ketogenic diets (KDs) are a promising alternative therapy for pediatric refractory epilepsy. Several predictors of KD responsiveness have been identified, including biochemical parameters, seizure types, and electroencephalography (EEG) examinations. We hypothesized that graph theory-based EEG functional connectivity could explain KD responses in patients presenting focal onset seizure (FOS). A total of 17 patients aged 0–30 years old with focal onset seizures (FOS) were recruited as a study group between January 2015 and July 2021. Twenty age-matched children presenting headache with no intracranial complications nor other medical issues were enrolled as a control group. Data were obtained at baseline and at 12 months after initiating KD therapy (KDT) using the child behavior checklist (CBCL) and brain functional connectivity parameters based on phase-locking value from 19 scalp EEG signals, including nodal strength, global efficiency, clustering coefficient, and betweenness centrality. Compared with age-matched controls, patients presenting FOS with right or bilateral EEG lateralization presented higher baseline functional connectivity, including parameters such as global efficiency, mean cluster coefficient and mean nodal strength in the delta and beta frequency bands. In patients presenting FOS with right or bilateral EEG lateralization, the global efficiency of functional connectivity parameters in the delta and theta frequency bands was significantly lower at 12 months after KDT treatment than before KDT. Those patients also presented a significantly lower mean clustering coefficient and mean nodal strength in the theta frequency band at 12 months after KDT treatment. Changes in brain functional connectivity were positively correlated with social problems, attention, and behavioral scores based on CBCL assessments completed by parents. This study provides evidence that KDT might be beneficial in the treatment of patients with FOS. Graph theoretic analysis revealed that the observed effects were related to decreased functional connectivity, particularly in terms of global efficiency. Our findings related to brain connectivity revealed lateralization to the right (non-dominant) hemisphere; however, we were unable to define the underlying mechanism. Our data revealed that in addition to altered brain connectivity, KDT improved the patient’s behavior and emotional state.
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