Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury

Abstract

Abstract Background Seizure is a common complication for severe traumatic brain injury (TBI). Valproic acid (VPA) is a first-line antiepileptic drug, though its metabolism is affected by genetic polymorphisms and varies between individuals. The aim of this study was to investigate such association and to explore its influence on the occurrence of early post-traumatic seizure. Methods A prospective case control study was conducted from 2012 to 2016 recruiting adult patients with severe TBI. Electroencephalograph (EEG) monitoring was performed approximately 4 h for each patient from day 1 to day 7 after injury. If seizures were detected, EEG monitoring was extended until 12 h after seizures being controlled. Genetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA plasma concentrations, adjusted dosages, and occurrence of seizures. Results Among the 395 recruited patients, eighty-three (21%) had early post-traumatic seizure, of which 30 (36.14%) were non-convulsive. Most seizures were first detected on day 1 (34.94%) and day 2 (46.99%) after injury. Patients with seizure had longer ICU length of stay and relatively lower VPA plasma concentrations. Patients with UGT1A6_19T > G/541A > G/552A > C double heterozygosities or CYP2C9 extensive metabolizers (EMs) initially had lower adjusted VPA plasma concentrations (power >0.99) and accordingly require higher VPA dosages during later time of treatment (power >0.99). The odds ratio indicated a higher risk of early post-traumatic seizure occurrence in male patients (OR 1.96, 95% CI 1.01-3.81, 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 heterozygosities (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. Discussion Due to limited facility, the actual frequency of non-convulsive seizures is suspected to be higher than identified. There has been discrepancy regarding to genetic polymorphisms and VPA metab olism between this study and some previous reports. This could be related to confounders such as sample size, race, and patient age. Another limitation is that the case numbers of certain genotypes are limited in this study. Conclusions Continuous EEG monitoring is necessary to detect both convulsive and non-convulsive early post-traumatic seizures in severe TBI patients. UGT1A6/CYP2C9 polymorphisms have influence on VPA metabolism. UGT1A6_19T > G/541A > G/552A > C double heterozygositie is associated with occurrence of early post-traumatic seizures in addition to patients’ age and gender. Further investigations with larger sample size are required to confirm the difference. Trial registration Retrospectively registered with Chinese Clinical Trail Registry on 1st Jan 2016 ( ChiCTR-OPC-16007687 )

Keywords

• Traumatic brain injury
• Valproic acid
• Seizure
• UGT1A6
• CYP2C9
• Genetic polymorphisms