Background: Seizure is a common complication for severe traumatic brain injury (TBI). Valproic acid (VPA) is a firstline\nantiepileptic drug, though its metabolism is affected by genetic polymorphisms and varies between individuals.\nThe aim of this study was to investigate such association and to explore its influence on the occurrence of early\npost-traumatic seizure.\nMethods: A prospective case control study was conducted from 2012 to 2016 recruiting adult patients with severe\nTBI. Electroencephalograph (EEG) monitoring was performed approximately 4 h for each patient from day 1 to day\n7 after injury. If seizures were detected, EEG monitoring was extended until 12 h after seizures being controlled.\nGenetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA\nplasma concentrations, adjusted dosages, and occurrence of seizures.\nResults: Among the 395 recruited patients, eighty-three (21%) had early post-traumatic seizure, of which 30 (36.14%)\nwere non-convulsive. Most seizures were first detected on day 1 (34.94%) and day 2 (46.99%) after injury. Patients with\nseizure had longer ICU length of stay and relatively lower VPA plasma concentrations. Patients with UGT1A6_19T > G/\n541A > G/552A > C double heterozygosities or CYP2C9 extensive metabolizers (EMs) initially had lower adjusted VPA\nplasma concentrations (power >0.99) and accordingly require higher VPA dosages during later time of treatment (power\n>0.99). The odds ratio indicated a higher risk of early post-traumatic seizure occurrence in male patients (OR 1.96, 95% CI\n1.01-3.81, p = 0.043), age over 65 (OR 2.13, 95% CI 1.01-4.48), and with UGT1A6_19T > G/541A > G/552A > C double\nheterozygosities (OR 2.38, 95% CI 1.11-5.10, p = 0.02), though the power of the difference was between 0.54 to 0.61.\nDiscussion: Due to limited facility, the actual frequency of non-convulsive seizures is suspected to be higher than\nidentified. There has been discrepancy regarding to genetic polymorphisms and VPA metab olism between this study\nand some previous reports. This could be related to confounders such as sample size, race, and patient age. Another\nlimitation is that the case numbers of certain genotypes are limited in this study.\nConclusions: Continuous EEG monitoring is necessary to detect both convulsive and non-convulsive early post-traumatic\nseizures in severe TBI patients. UGT1A6/CYP2C9 polymorphisms have influence on VPA metabolism. UGT1A6_19T > G/\n541A > G/552A > C double heterozygositie is associated with occurrence of early post-traumatic seizures in addition to\npatients� age and gender. Further investigations with larger sample size are required to confirm the difference.
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