Summary Introduction Seizures are known to perturb circadian rhythms in humans as well as in animal models of epilepsy. However, it is unknown whether treatment of the underlying epilepsy restores normal biological rhythms. We asked whether: (1) seizure activity is characterized by diurnal rhythmicity; (2) chronically epileptic mice exhibit impaired activity-rest rhythms; and (3) treatment with the anticonvulsant ketogenic diet (KD) improves such perturbations. Methods Chronically epileptic Kcna1-null mice were fed either a standard diet or KD for 4 wks and subjected to continuous video-EEG and actigraphy monitoring for 3–5 days to assess seizure activity and rest-activity cycles. Results Seizure activity in Kcna1-null mice demonstrated diurnal rhythmicity, peaking at zeitgeber (ZT) 2.30±1.52. Activity-rest rhythms of epileptic mice were significantly disrupted. Whereas locomotor activity for wild-type mice peaked at ZT15.45±0.28 (ZT14:26–ZT16:51), peak activity of epileptic mice was more unpredictable, occurring over a 12.4hr range (ZT06:33–ZT18:57). In 6 of 9 epileptic mice, peak activity was delayed to ZT17.42±0.38, while peak activity was advanced to ZT10.00±1.26 in the remaining mice. Treatment with the KD abolished seizure periodicity and restored the activity-rest rhythm to values resembling those of wild-type mice (i.e. activity peaking at ZT16.73±0.67). Conclusions Kcna1-null mice experience seizures with 24-hr periodicity and impaired circadian behavior. KD reduces the number and periodicity of seizures and restores normal behavioral rhythms, suggesting that this non-pharmacological therapy may benefit biological rhythm disturbances in epileptic patients.

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