REFERENCES
between groups, the only significant adverse event noted for patients receiving phenytoin was irritation at the infusion site (n = 7); however, patients in the fosphenytoin group experienced adverse events including: cardiovascular (n = 2), CNS symptoms (n = 7), cutaneous symptoms (n = 19), and other symptoms (n = 4). In addition, fosphenytoin did not decrease the ED length of stay. While specific conclusions regarding the safety of fosphenytoin for posttraumatic seizure prophylaxis cannot be drawn, fosphenytoin did not improve safety or reduce length of stay in the emergency department in this study. Two additional articles used data from a randomized controlled trial (NCT00618436). 20,21 One study compared levetiracetam to phenytoin for seizure prophylaxis 21 and the other examined whether initial EEG predicted outcomes in a trial comparing levetiracetam to fosphenytoin. 20 These two studies used the same patient population and a loading dose of fosphenytoin, 20mg/kg PE IV over 60 minutes, followed by a maintenance dose of phenytoin (5 mg/kg/day, rounded to the nearest 100 mg dose). The design of this study precludes any analysis of safety of fosphenytoin for primary early seizure prophylaxis patients with TBI.
1. Administration FaD. Dilantin (phenytoin sodium USP) Injection Prescribing Informatoin, March 2013. 2013; http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/010151s037lbl.pdf. Accessed 3/9/2017, 2017. 2. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497-502. 3. Bhullar IS, Johnson D, Paul JP, et al. 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. 4. Rish BL, Caveness WF. Relation of prophylactic medication to the occurrence of early seizures following craniocerebral trauma. J Neurosurg. 1973;38(2):155-158. 5. Young B, Rapp RP, Norton JA, et al. Failure of prophylactically administered phenytoin to prevent late posttraumatic seizures. J Neurosurg. 1983;58(2):236-241. 6. Brain Trauma Foundation AAoNS, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma. 2007;24 (Suppl 1):S83-S86. 7. Boucher BA. Fosphenytoin: a novel phenytoin prodrug. Pharmacotherapy. 1996;16(5):777-791. 8. Ramsay RE, DeToledo J. Intravenous administration of fosphenytoin: options for the management of seizures. Neurology. 1996;46(6 Suppl 1):S17-19. 9. Administration USFaD. Dilantin (phenytoin). 2017; https://www.fda. gov/Safety/MedWatch/SafetyInformation/ucm243476.htm. Accessed 3/9/2017, 2017. 10. Scheinfeld N. Impact of phenytoin therapy on the skin and skin disease. Expert Opin Drug Saf. 2004;3(6):655-665. 11. Lee HY, ChungWH. Toxic epidermal necrolysis: the year in review. Curr Opin Allergy Clin Immunol. 2013;13(4):330-336. 12. Harr T, French LE. Stevens-Johnson syndrome and toxic epidermal necrolysis. Chem Immunol Allergy. 2012;97:149-166. 13. Cheng CY, Su SC, Chen CH, Cet al. HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions: an updated review. J Immunol Res. 2014;2014:565320. 14. Cheung YK, Cheng SH, Chan EJ, et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia. 2013;54(7):1307-1314. 15. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol . 2013;133(5):1197-1204. 16. Dikmen SS, Temkin NR, Miller B, et al. Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures. JAMA . 1991;265(10):1271-1277. 17. Kruer RM, Harris LH, Goodwin H, 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 e889-813. 18. Al-Quteimat OM. Phenytoin-induced toxic epidermal necrolysis: Review and recommendations. J Pharmacol Pharmacother . 2016;7(3):127-132. 19. Coplin WM, Rhoney DH, Rebuck JA, et al. Randomized evaluation of adverse events and length-of-stay with routine emergency department use of phenytoin or fosphenytoin. Neurol Res . 2002;24(8):842-848. 20. Steinbaugh LA, Lindsell CJ, Shutter LA, et al. Initial EEG predicts outcomes in a trial of levetiracetam vs. fosphenytoin for seizure prevention. Epilepsy Behav. 2012;23(3):280-284. 21. Szaflarski JP, Sangha KS, Lindsell CJ, et al. Prospective, randomized, single- blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12(2):165-172.
CONCLUSION
In the current case, primary seizure prophylaxis after traumatic brain injury with fosphenytoin resulted in TEN and a seven week stay in a burn unit, marked by serious, life-threating complications. This case report highlights the paucity of research on the safety and efficacy of fosphenytoin for primary posttraumatic seizure prophylaxis and the need for physicians to consider the risk/benefit ratio of pottraumatic seizure prophylaxis in light of little empirical support. Furthermore, there is evidence to suggest that some patients may be genetically predisposed to greater risks of adverse reactions when treated with antiepileptic medications. 13,14 While genetic testing was not completed on this patient, he was Chinese, suggesting he may have been at significantly higher risk for developing a severe adverse reaction. As we learn more about pharmacogenetics, we should incorporate this empirical evidence into our practice. In sum, it is questionable whether there is any benefit from treating patients with anticonvulsants after TBI, but there is no question that primary seizure prophylaxis, like all medications, carries the potential for harm. Given the lack of evidence of improved outcomes for primary seizure prophylaxis after TBI and the potential for severe adverse events such as SJS and TEN, the guidelines may require reconsideration. At the very least, patient-specific variables such as ethnic variability that place patients at greater risk for severe adverse reactions should be considered prior to initiation of primary posttraumatic seizure prophylaxis.
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