In gratitude of the loyal support of our members, the CNS is offering complimentary 2021 Annual Meeting registration to all members! Learn more.

  • Early Post-Traumatic Seizures are Associated with Valproic Acid Plasma Concentrations and UGT1A6/CYP2C9 Genetic Polymorphisms in Patients with Severe Traumatic Brain Injury

    Final Number:

    Yirui Sun MD PhD; Jian Yu MD; qiang yuan; Jin Hu

    Study Design:
    Clinical Trial

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting

    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.

    References: 1. Annegers JF, Hauser WA, Coan SP, Rocca WA: A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998, 338:20-24. 2. Vespa PM, Nuwer MR, Nenov V, Ronne-Engstrom E, Hovda DA, Bergsneider M, Kelly DF, Martin NA, Becker DP: Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J Neurosurg 1999, 91:750-760. 3. Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ: Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004, 62:1743-1748. 4. Jordan KG: Continuous EEG and evoked potential monitoring in the neuroscience intensive care unit. J Clin Neurophysiol 1993, 10:445-475. 5. Vespa PM, Nenov V, Nuwer MR: Continuous EEG monitoring in the intensive care unit: early findings and clinical efficacy. J Clin Neurophysiol 1999, 16:1-13. 6. Tay SK, Hirsch LJ, Leary L, Jette N, Wittman J, Akman CI: Nonconvulsive status epilepticus in children: clinical and EEG characteristics. Epilepsia 2006, 47:1504-1509. 7. Vespa PM, Miller C, McArthur D, Eliseo M, Etchepare M, Hirt D, Glenn TC, Martin N, Hovda D: Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis. Crit Care Med 2007, 35:2830-2836. 8. Thapa A, Chandra SP, Sinha S, Sreenivas V, Sharma BS, Tripathi M: Post-traumatic seizures-A prospective study from a tertiary level trauma center in a developing country. Seizure 2010, 19:211-216. 9. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, et al: Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2016. 10. Chadwick DW: Concentration-effect relationships of valproic acid. Clin Pharmacokinet 1985, 10:155-163. 11. DeVane CL: Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003, 37 Suppl 2:25-42. 12. Ebner T, Burchell B: Substrate specificities of two stably expressed human liver UDP-glucuronosyltransferases of the UGT1 gene family. Drug Metab Dispos 1993, 21:50-55. 13. Jin C, Miners JO, Lillywhite KJ, Mackenzie PI: Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther 1993, 264:475-479. 14. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther 2008, 83:595-600. 15. Klotz U: The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet 2007, 46:271-279. 16. Loscher W, Klotz U, Zimprich F, Schmidt D: The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia 2009, 50:1-23. 17. Kiang TK, Ho PC, Anari MR, Tong V, Abbott FS, Chang TK: Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol Sci 2006, 94:261-271. 18. Innocenti F, Liu W, Fackenthal D, Ramirez J, Chen P, Ye X, Wu X, Zhang W, Mirkov S, Das S, et al: Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics 2008, 18:683-697. 19. Nagar S, Zalatoris JJ, Blanchard RL: Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells. Pharmacogenetics 2004, 14:487-499. 20. Ibarra M, Vazquez M, Fagiolino P, Derendorf H: Sex related differences on valproic acid pharmacokinetics after oral single dose. J Pharmacokinet Pharmacodyn 2013, 40:479-486. 21. Birnbaum AK, Ahn JE, Brundage RC, Hardie NA, Conway JM, Leppik IE: Population pharmacokinetics of valproic acid concentrations in elderly nursing home residents. Ther Drug Monit 2007, 29:571-575. 22. AAAM: Abbreviated Injury Scale (AIS) 2005 Manual. 1 edn: Association for the Advancement of Automotive Medicine; 2005. 23. Demetriades D, Kuncir E, Murray J, Velmahos GC, Rhee P, Chan L: Mortality prediction of head Abbreviated Injury Score and Glasgow Coma Scale: analysis of 7,764 head injuries. J Am Coll Surg 2004, 199:216-222. 24. Zehtabchi S, Soghoian S, Liu Y, Carmody K, Shah L, Whittaker B, Sinert R: The association of coagulopathy and traumatic brain injury in patients with isolated head injury. Resuscitation 2008, 76:52-56. 25. Alvarez M, Nava JM, Rue M, Quintana S: Mortality prediction in head trauma patients: performance of Glasgow Coma Score and general severity systems. Crit Care Med 1998, 26:142-148. 26. Brain Trauma F, American Association of Neurological S, Congress of Neurological S: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2007, 24 Suppl 1:S1-106. 27. Chu XM, Zhang LF, Wang GJ, Zhang SN, Zhou JH, Hao HP: Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur J Clin Pharmacol 2012, 68:1395-1401. 28. Tan L, Yu JT, Sun YP, Ou JR, Song JH, Yu Y: The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin Neurol Neurosurg 2010, 112:320-323. 29. Guo Y, Hu C, He X, Qiu F, Zhao L: Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab Pharmacokinet 2012, 27:536-542. 30. Dikmen SS, Machamer JE, Winn HR, Anderson GD, Temkin NR: Neuropsychological effects of valproate in traumatic brain injury: a randomized trial. Neurology 2000, 54:895-902. 31. Noai M, Soraoka H, Kajiwara A, Tanamachi Y, Oniki K, Nakagawa K, Ishitsu T, Saruwatari J: Cytochrome P450 2C19 polymorphisms and valproic acid-induced weight gain. Acta Neurol Scand 2016, 133:216-223. 32. Sutter R, Semmlack S, Kaplan PW: Nonconvulsive status epilepticus in adults - insights into the invisible. Nat Rev Neurol 2016, 12:281-293. 33. Tankanitlert J, Morales NP, Howard TA, Fucharoen P, Ware RE, Fucharoen S, Chantharaksri U: Effects of combined UDP-glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on paracetamol pharmacokinetics in beta-thalassemia/HbE. Pharmacology 2007, 79:97-103. 34. Wang SL, Huang J, Lai MD, Tsai JJ: Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 1995, 5:37-42. 35. Ronne-Engstrom E, Winkler T: Continuous EEG monitoring in patients with traumatic brain injury reveals a high incidence of epileptiform activity. Acta Neurol Scand 2006, 114:47-53. 36. Duncan R, Oto M, Martin E, Pelosi A: Late onset psychogenic nonepileptic attacks. Neurology 2006, 66:1644-1647. 37. Xing Y, Yang L, Wang L, Shao L, Wei Z, Xuan J, Li J, Qin S, Shu A, He L, Xing Q: Systematic screening for polymorphisms within the UGT1A6 gene in three Chinese populations and function prediction through structural modeling. Pharmacogenomics 2009, 10:741-752. 38. Lin GF, Guo WC, Chen JG, Qin YQ, Golka K, Xiang CQ, Ma QW, Lu DR, Shen JH: An association of UDP-glucuronosyltransferase 2B7 C802T (His268Tyr) polymorphism with bladder cancer in benzidine-exposed workers in China. Toxicol Sci 2005, 85:502-506. 39. Yang JQ, Morin S, Verstuyft C, Fan LA, Zhang Y, Xu CD, Barbu V, Funck-Brentano C, Jaillon P, Becquemont L: Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations. Fundam Clin Pharmacol 2003, 17:373-376. 40. Hung CC, Ho JL, Chang WL, Tai JJ, Hsieh TJ, Hsieh YW, Liou HH: Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics 2011, 12:1107-1117. 41. Chatzistefanidis D, Lazaros L, Giaka K, Nakou I, Tzoufi M, Georgiou I, Kyritsis A, Markoula S: UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels. Pharmacogenomics 2016, 17:827-835. 42. Jiang D, Bai X, Zhang Q, Lu W, Wang Y, Li L, Muller M: Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling. Eur J Clin Pharmacol 2009, 65:1187-1193. 43. Sanchez MB, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizan EM, Nicolas JM, Adin J, Armijo JA: Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy. Seizure 2010, 19:93-101. 44. Amini-Shirazi N, Ghahremani MH, Ahmadkhaniha R, Mandegary A, Dadgar A, Abdollahi M, Shadnia S, Pakdaman H, Kebriaeezadeh A: Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients. Toxicol Mech Methods 2010, 20:452-457.

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy