Introduction: 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 case control study was conducted from 2012 to 2016 recruiting adult patients with severe TBI. Continuous electroencephalograph (EEG) monitoring was performed for 7 days. Genetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA plasma concentrations, adjusted dosages, and occurrence seizures.

Results: Among the 395 recruited patients, eight-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).

Conclusions: Continuous EEG monitoring are 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.

Patient Care: Early post-traumatic seizure (within 7 days of injury) is a major complication of severe traumatic brain injury (TBI), accounting for increased morbidity and elevated risk of death. Valproic acid is a first line anti-convulsive drug, but its effects depends on plasma concentrations that vary between individuals. Based on our observation, we have proven the importance of continuous EEG monitoring for detecting both convulsive and non-convulsive seizures. We would also advocate a routine screen of UGT/CYP polymorphisms for severe TBI patients, as their mutations affected VPA plasma concentrations. Male patients and age over 65 shall also be paid close attention to, as they have a higher chance of developing early post-traumatic seizures.

Learning Objectives: Continuous EEG monitoring were necessary to detect convulsive and non-convulsive post-traumatic seizures in patients with severe TBI. VPA metabolism were affected by UGT1A6/CYP2C9 mutations. It would be worthwhile to perform UGT/CYP polymorphisms screen and VPA plasma concentration monitoring within 7 days after injury. Male patients, age over 65, and with UGT1A6_19T>G/541A>G/552A>C double heterozygosities had higher risk of early post-traumatic seizures, but further investigations with larger sample size are required to better illustrate the difference.

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