CNS Drugs

, Volume 30, Issue 8, pp 677–688 | Cite as

Levetiracetam Versus Phenytoin for Seizure Prophylaxis Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis

  • Yong Yang
  • Fangshuo Zheng
  • Xin Xu
  • Xuefeng WangEmail author
Systematic Review



Seizure following traumatic brain injury (TBI) constitutes a common complication that requires effective prevention to improve the outcome of TBI. Phenytoin has been the only recommended antiepileptic drug (AED) for seizure prophylaxis; however, several shortcomings have affected its use. Intravenous levetiracetam has been available since 2006 and has been increasingly accepted as a seizure prophylaxis for brain injury, mainly due to its favorable pharmacokinetic features and minimal adverse events profile. However, the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI are not well clarified.


The aim of this study was to assess the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI.


We conducted a search of the MEDLINE, EMBASE, and Cochrane library databases to March 2016, and screened original research that included patients with TBI who received levetiracetam. We included randomized controlled trials (RCTs) or controlled observational cohort studies that compared levetiracetam and phenytoin, as well as uncontrolled case series regarding prophylactic levetiracetam following TBI. The outcomes included early or late seizure prophylaxis and safety. The estimates of seizure prophylaxis were pooled using a meta-analysis, and the estimates for the case series were pooled using descriptive statistics.


A total of 1614 patients from 11 studies were included in this review, of whom 1285 patients from eight controlled studies (one RCT and seven cohort studies) were included in the meta-analysis. Levetiracetam was not superior to phenytoin with regard to early seizure prophylaxis (risk ratio [RR] 1.10, 95 % confidence interval [CI] 0.64–1.88); the estimate of early seizure incidence was 0.05 (95 % CI 0.02–0.08). Three studies that assessed late seizure did not indicate the superiority of levetiracetam to phenytoin. There were no differences in mortality during hospitalization or after 6 months, or in the number of patients with adverse reactions between levetiracetam and phenytoin.


Levetiracetam does not appear to be superior to phenytoin in efficacy or safety with regard to early or late seizure prophylaxis following TBI; however, no class I evidence was identified. Additional evidence from high-quality studies is required.


Traumatic Brain Injury Glasgow Coma Scale Levetiracetam Severe Traumatic Brain Injury Ottawa Scale 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


This study was supported by the National Natural Science Foundation of China (Grant Numbers 81271445 and 81501122) and the National Clinical Key Specialty Construction Foundation of China.

Conflicts of interest

Yong Yang, Fangshuo Zheng, Xin Xu and Xuefeng Wang declare that they have no conflicts of interest.

Supplementary material

40263_2016_365_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)


  1. 1.
    Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.Google Scholar
  2. 2.
    Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998;338(1):20–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing late seizures and influence of seizures on long-term outcome. Epilepsia. 1999;40(5):584–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Annegers JF, Grabow JD, Groover RV, Laws ER Jr, Elveback LR, Kurland LT. Seizures after head trauma: a population study. Neurology. 1980;30(7):683–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Guilliams K, Wainwright MS. Pathophysiology and management of moderate and severe traumatic brain injury in children. J Child Neurol. 2016;31(1):35–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Szaflarski JP, Nazzal Y, Dreer LE. Post-traumatic epilepsy: current and emerging treatment options. Neuropsychiatr Dis Treat. 2014;10:1469–77.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Loscher W, Brandt C. Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev. 2010;62(4):668–700.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wyllie E. Wyllie’s treatment of epilepsy. 5th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2010.Google Scholar
  9. 9.
    Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;60(1):10–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma. 2007;24(Suppl 1):S83–6.PubMedGoogle Scholar
  11. 11.
    Fuller KL, Wang YY, Cook MJ, Murphy MA, D’Souza WJ. Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia. 2013;54(1):45–57.CrossRefPubMedGoogle Scholar
  12. 12.
    Bhullar IS, Johnson D, Paul JP, Kerwin AJ, Tepas JJ 3rd, Frykberg ER. More harm than good: antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery. J Trauma Acute Care Surg. 2014;76(1):54–60 (discussion 60–51).CrossRefPubMedGoogle Scholar
  13. 13.
    Virant-Young D, Alexander R, Umstead G, Savoy-Moore R, Himes D, Nikolavsky M, et al. Retrospective analysis of phenytoin and levetiracetam for seizure prophylaxis after traumatic brain injury. Crit Care Med. 2009;37(12):A443.Google Scholar
  14. 14.
    Pourzitaki C, Tsaousi G, Apostolidou E, Karakoulas K, Kouvelas D, Amaniti E. Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016. doi: 10.1111/bcp.12926 (Epub 5 Mar 2016).PubMedGoogle Scholar
  15. 15.
    Iuchi T, Kuwabara K, Matsumoto M, Kawasaki K, Hasegawa Y, Sakaida T. Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. J Neurol Neurosurg Psychiatry. 2015;86(10):1158–62.CrossRefPubMedGoogle Scholar
  16. 16.
    Rowe AS, Goodwin H, Brophy GM, Bushwitz J, Castle A, Deen D, et al. Seizure prophylaxis in neurocritical care: a review of evidence-based support. Pharmacotherapy. 2014;34(4):396–409.CrossRefPubMedGoogle Scholar
  17. 17.
    Thompson K, Pohlmann-Eden B, Campbell LA, Abel H. Pharmacological treatments for preventing epilepsy following traumatic head injury. Cochrane Database Syst Rev. 2015;8:CD009900.PubMedGoogle Scholar
  18. 18.
    Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. Accessed Nov 2013.
  19. 19.
    Anderson R, Montero J. Utilization of seizure prophylaxis in traumatic brain injury (TBI) patients. Crit Care Med. 2014;42(12):A1626.CrossRefGoogle Scholar
  20. 20.
    Caballero GC, Hughes DW, Maxwell PR, Green K, Gamboa CD, Barthol CA. Retrospective analysis of levetiracetam compared to phenytoin for seizure prophylaxis in adults with traumatic brain injury. Hosp Pharm. 2013;48(9):757–61.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Carter D, Askari R, Frawley B, Rogers S. Evaluation of the use of phenytoin and levetiracetam for seizure prophylaxis in patients with traumatic brain injury. Crit Care Med. 2009;37(12):A77.Google Scholar
  22. 22.
    Chung MG, O’Brien NF. Prevalence of early posttraumatic seizures in children with moderate to severe traumatic brain injury despite levetiracetam prophylaxis. Pediatr Crit Care Med. 2016;17(2):150–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Gabriel WM, Rowe AS. Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after traumatic brain injury. Ann Pharmacother. 2014;48(11):1440–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Inaba K, Menaker J, Branco BC, Gooch J, Okoye OT, Herrold J, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013;74(3):766–71 (discussion 771–763).CrossRefPubMedGoogle Scholar
  25. 25.
    Jones KE, Puccio AM, Harshman KJ, Falcione B, Benedict N, Jankowitz BT, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25(4):E3.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Klein P, Herr D, Pearl PL, Natale J, Levine Z, Nogay C, et al. Results of phase 2 safety and feasibility study of treatment with levetiracetam for prevention of posttraumatic epilepsy. Arch Neurol. 2012;69(10):1290–5.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kruer RM, Harris LH, Goodwin H, Kornbluth J, Thomas KP, Slater LA, et al. Changing trends in the use of seizure prophylaxis after traumatic brain injury: a shift from phenytoin to levetiracetam. J Crit Care. 2013;28(5):883.CrossRefPubMedGoogle Scholar
  28. 28.
    Patanwala AE, Kurita A, Truong E. Low-dose levetiracetam for seizure prophylaxis after traumatic brain injury. Brain Inj. 2016;30(2):156–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12(2):165–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Schierhout G, Roberts I. Prophylactic antiepileptic agents after head injury. A systematic review. J Neurol Neurosurg Psychiatry. 1998;64(1):108–12.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Glotzner FL, Haubitz I, Miltner F, Kapp G, Pflughaupt KW. Seizure prevention using carbamazepine following severe brain injuries [in German]. Neurochirurgia (Stuttg). 1983;26(3):66–79.PubMedGoogle Scholar
  32. 32.
    Temkin NR, Dikmen SS, Anderson GD, Wilensky AJ, Holmes MD, Cohen W, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg. 1999;91(4):593–600.CrossRefPubMedGoogle Scholar
  33. 33.
    Pechadre JC, Lauxerois M, Colnet G, Commun C, Dimicoli C, Bonnard M, et al. Prevention of late post-traumatic epilepsy by phenytoin in severe brain injuries. 2 years’ follow-up [in French]. Presse Med. 1991;20(18):841–5.PubMedGoogle Scholar
  34. 34.
    Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497–502.CrossRefPubMedGoogle Scholar
  35. 35.
    Young B, Rapp RP, Norton JA, Haack D, Tibbs PA, Bean JR. Failure of prophylactically administered phenytoin to prevent early posttraumatic seizures. J Neurosurg. 1983;58(2):231–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Young KD, Okada PJ, Sokolove PE, Palchak MJ, Panacek EA, Baren JM, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med. 2004;43(4):435–46.CrossRefPubMedGoogle Scholar
  37. 37.
    McQueen JK, Blackwood DH, Harris P, Kalbag RM, Johnson AL. Low risk of late post-traumatic seizures following severe head injury: implications for clinical trials of prophylaxis. J Neurol Neurosurg Psychiatry. 1983;46(10):899–904.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Winter ME. Phenytoin and fosphenytoin. In: Murphy JE, editor. Clinical pharmacokinetics. Bethesda: American Society of Health-System Pharmacists; 2008. p. 247–64.Google Scholar
  39. 39.
    Zafar SN, Khan AA, Ghauri AA, Shamim MS. Phenytoin versus leviteracetam for seizure prophylaxis after brain injury: a meta analysis. BMC Neurol. 2012;12:30.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Shah D, Husain AM. Utility of levetiracetam in patients with subarachnoid hemorrhage. Seizure. 2009;18(10):676–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Jones GL, Wimbish GH, McIntosh WE. Phenytoin: basic and clinical pharmacology. Med Res Rev. 1983;3(4):383–434.CrossRefPubMedGoogle Scholar
  42. 42.
    De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam. part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev. 2007;13(1):57–78.CrossRefPubMedGoogle Scholar
  43. 43.
    Cotton BA, Kao LS, Kozar R, Holcomb JB. Cost-utility analysis of levetiracetam and phenytoin for posttraumatic seizure prophylaxis. J Trauma. 2011;71(2):375–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Pieracci FM, Moore EE, Beauchamp K, Tebockhorst S, Barnett CC, Bensard DD, et al. A cost-minimization analysis of phenytoin versus levetiracetam for early seizure pharmacoprophylaxis after traumatic brain injury. J Trauma Acute Care Surg. 2012;72(1):276–81.CrossRefPubMedGoogle Scholar
  45. 45.
    Hahn YS, Fuchs S, Flannery AM, Barthel MJ, McLone DG. Factors influencing posttraumatic seizures in children. Neurosurgery. 1988;22(5):864–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Henry PC, Hauber RP, Rice M. Factors associated with closed head injury in a pediatric population. J Neurosci Nurs. 1992;24(6):311–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Pentland B, Jones PA, Roy CW, Miller JD. Head injury in the elderly. Age Ageing. 1986;15(4):193–202.CrossRefPubMedGoogle Scholar
  48. 48.
    Haltiner AM, Temkin NR, Dikmen SS. Risk of seizure recurrence after the first late posttraumatic seizure. Arch Phys Med Rehabil. 1997;78(8):835–40.CrossRefPubMedGoogle Scholar
  49. 49.
    Szaflarski JP. Is there equipoise between phenytoin and levetiracetam for seizure prevention in traumatic brain injury? Epilepsy Curr. 2015;15(2):94–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Yong Yang
    • 1
  • Fangshuo Zheng
    • 1
  • Xin Xu
    • 1
  • Xuefeng Wang
    • 1
    • 2
    Email author
  1. 1.Department of Neurology, Chongqing Key Laboratory of NeurologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Center of EpilepsyBeijing Institute for Brain DisordersBeijingChina

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