Twenty‐four hour pattern of childhood febrile seizures substantiated by time series meta‐analysis: Circadian medicine perspectives

Abstract Major objectives of this work were to: (1) substantiate the 24‐hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta‐analysis of past reported time‐of‐day data and (2) discuss its potential circadian rhythm‐dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population‐mean cosinor analysis validated ( p < .001) a 24‐hour pattern in the onset of CFSs, with an approximate four‐fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40–19:07 h) vs trough at 06:00 h, in the absence of meaningful time‐of‐day differences in mean body temeprarure. The CFS time‐of‐day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable‐in‐time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time‐of‐day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.