Introduction: Seizure is one of the most common complications for neurocritical patients, and failure to control seizures is often associated with increased physical and psychosocial morbidity, as well as an elevated risk of death. Valproic acid (VPA) is widely used as prophylactic treatment for seizure. Although VPA is affordable and effective, there is large interindividual variability in its effects due to difference in pharmacokinetics and pharmacodynamics, and its plasma concentration often needs to be monitored during the course of therapy. These differences in VPA dose and plasma concentration may re?ect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes, which involves three major metabolic pathways, glucuronidation conjugation (mainly mediated by UGT1A6 and UGT2B7), mitochrondrial oxidation, and CYP-catalyzed terminal desaturation and hydroxylation (mainly mediated by CYP2C9). However, the incidence of seizure among neurocritical patients with different genetic polymorphisms have not been determined and recommended dose adjustment remains unclear.
Methods: Two hundred and fifty-six neurocritical patients (mostly with neurotrauma and intracranical hemorrhage) were enrolled in this prospective study. Informed consent was obtained from all participants and the study complied with the guidelines of the Medical Ethical Committee. The genetic polymorphisms of UGT1A6, UGT2B7, and CYP2C9 were analyzed for each patients and bedside neuro-electrophysiological monitoring was applied to detect seizure attack. VPA plasma concentrations were also measured for each patients. Finally, we established a model to optimize VPA dosage application according to patients’ personalized genetic polymorphisms.
Results: By monitoring bedside electrophysiological data, we found 5.3% patients had convulsions under routine prophylactic treatment. Over 14.5% neurocritical patients had at least once non-convulsive seizures. By adapting mathematics modeling, we adjust VPA dosage for each neurocritical patient during their early stage of treatment according to personalized genetic polymorphisms data. Since we applied such strategy, the incidence of seizure, particularly non-convulsive seizures significantly decreased, along with more stable VPA plasma concentrations.
Conclusions: Seizure, particularly non-convulsive seizure is a common complication for neurocritical patients. Genetic polymorphisms lead to interindividual variability in pharmacokinetics and pharmacodynamics, which is critical for anti-seizure therapy and outcome. By analyzing individual genetic polymorphisms, it is possible to adapt personalized dosage adjustment and achieve better outcome for patients.
Patient Care: Completing the study would help to determine the incidence of seizure/non-convulsive seizures among neurocritical patients with different genetic polymorphisms. By analyzing the relationship between genetic variations and VPA plasma concentrations, it is possible to achieve personalized anti-seizure treatment and better outcome.
Learning Objectives: To understand seizure is one of the most common and threatening complications for neurocritical patients. Failure of preventing seizure is sometimes due to genetic polymorphisms affecting pharmacokinetics and pharmacodynamics. By adapting personalized treatment, incidence of seizure could be down regulated as long as to achieve better outcome.