Seizure Prophylaxis in Traumatic Brain Injury

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. The Brain Trauma Foundation updated its guidelines for the management of severe TBI in 2016; however, there remains a lack of randomized clinical trials addressing many aspects of care in TBI patients.

Key Points on Seizure Prophylaxis in TBI

The incidence of early post-traumatic seizures may be as high as 30 percent in patients with severe TBI
Antiseizure medications in acute management of TBI have been shown to reduce incidence of early seizures but have not been shown to prevent later development of epilepsy
Prevention of early seizures is beneficial to prevent status epilepticus and further aggravation of systemic injury
The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury; however, levetiracetam is commonly used in this setting

Pharmacology Comparison

Parameter	Phenytoin	Valproic Acid	Levetiracetam	Lacosamide
Dose	Load: 17–20 mg/kg IV (max 2 g) Maint: 100 mg q8h or 5 mg/kg/day divided q8h (max single dose 400 mg) Duration not to exceed 7 days	10–15 mg/kg/day	Load: 20 mg/kg IV over 5–20 min Maint: 1 g IV over 15 min q12h for 7 days (may increase to 1.5 g q12h)	50–100 mg IV twice daily May give loading dose of 200 mg
Administration	IV piggyback rate of ≤50 mg/min	IV piggyback over 60 min at rate ≤20 mg/min	IV push or piggyback over 5–20 min	Bolus: undiluted at ≤80 mg/min Infusion: over 30–60 min
PK/PD	Onset: 30 min – 1 hr t½: 10–12 hrs	Peak: <1 hr t½: 9–19 hrs	Peak: 5–30 min t½: 6–8 hrs	Peak: <1 hr t½: ~13 hrs
Adverse Effects	Hematologic Cardiovascular CNS Gingival hyperplasia Hepatotoxicity	CNS Hematologic Hepatotoxicity Encephalopathy Pancreatitis	CNS depression Hypersensitivity Psychiatric/Behavioral Increased BP	Cardiac arrhythmias Bradycardia AV block CNS effects
Warnings	Vesicant, acute toxicity risk	Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma	Caution in renal impairment	Administer loading doses under medical supervision due to increased CNS adverse reactions

Clinical Pearl

While phenytoin remains the guideline-recommended agent, levetiracetam offers a more favorable side-effect profile and does not require drug level monitoring. Valproic acid is explicitly not recommended for post-traumatic seizure prophylaxis in acute head trauma.

Guideline Recommendation

Guideline	Recommendation
Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition – 2017	Phenytoin is recommended to decrease the incidence of early PTS (within 7 days of injury), when the overall benefit is thought to outweigh the complications associated with treatment. There is insufficient evidence to recommend levetiracetam compared with phenytoin regarding efficacy in preventing early post-traumatic seizures and toxicity.

Guideline

Recommendation

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition – 2017

Phenytoin is recommended to decrease the incidence of early PTS (within 7 days of injury), when the overall benefit is thought to outweigh the complications associated with treatment.

There is insufficient evidence to recommend levetiracetam compared with phenytoin regarding efficacy in preventing early post-traumatic seizures and toxicity.

Overview of Key Evidence

7 Studies

Author / Year	Design (n)	Intervention	Key Findings
Temkin, 1990⁵	RCT (DB) n=404	Phenytoin vs Placebo	3.6% vs 14.2% seizure at 7d (p<0.001) Phenytoin is effective in reducing seizures within the first 7 days after severe head injury. No benefit beyond day 7.
Young, 2004⁶	RCT (DB, PC) n=102 (pediatric)	Phenytoin vs Placebo in pediatric patients (<16 yo)	7% vs 5% seizure at 48h (NS) Phenytoin did not significantly reduce posttraumatic seizures at 48 hours, neurologic outcomes, or survival at 30 days.
Jones, 2008⁷	Prospective n=32	Phenytoin vs Levetiracetam in severe TBI (GCS 3–8)	Equivalent seizure incidence (p=0.556) LEV as effective as PHT for preventing early seizures but associated with increased seizure tendency on EEG (p=0.003).
Szaflarski, 2009⁸	RCT (SB) n=52	Levetiracetam vs Phenytoin in severe TBI or SAH	Better long-term outcomes with LEV No seizure difference. Lower frequency of worsened neuro status (p=0.024) and GI problems (p=0.043) with LEV.
Inaba, 2012¹⁰	Prospective n=1,191 Largest	Levetiracetam vs Phenytoin for early PTS prevention	1.5% vs 1.5% (p=0.997) No difference between LEV and PHT in prevention of early PTS, mortality, or ADRs.
Caballero, 2013¹¹	Retrospective n=90	Phenytoin vs Levetiracetam in TBI with EEG monitoring	28% vs 29% seizure (p=0.99) Lower cost with LEV LEV may be an alternative while providing lower costs ($43 vs $55/day, p=0.08).
Khan, 2016¹⁴	RCT n=154	Phenytoin vs Levetiracetam in moderate–severe head trauma	94.8% vs 90.9% efficacy (NS) No statistically significant difference in efficacy of PHT and LEV for early PTS prophylaxis.

Clinical Conclusions

Bottom Line

Phenytoin remains the guideline-recommended agent for early post-traumatic seizure prophylaxis (7 days), but levetiracetam shows equivalent efficacy with fewer side effects. Neither agent prevents late-onset epilepsy.

The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury; however, levetiracetam is commonly used in this setting.

In recent studies, lacosamide and levetiracetam showed no difference compared to phenytoin in prevention of early post-traumatic seizures following TBI.

Fewer side effects were associated with levetiracetam and lacosamide compared to phenytoin when used in seizure prophylaxis in TBI.

Full Reference List

14 refs

Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved October 17, 2023.
Carney N, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15.
Frey LC. Epidemiology of Posttraumatic Epilepsy: A critical review. Epilepsia. 2003;44(s10):11-17.
Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved October 13, 2023.
Temkin NR, 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.
Young KD, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children. Ann Emerg Med. 2004;43(4):435-446.
Jones KE, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25(4):E3.
Szaflarski JP, et al. Seizure control in patients with epilepsies: EEG determinants of medication response. Epilepsy Behav. 2010;17(4):525-530.
Ma CY, et al. Sodium valproate for prevention of early posttraumatic seizures. Chin J Traumatol. 2010;13(5):293-296.
Inaba K, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013;74(3):766-773.
Caballero GC, et al. Retrospective analysis of levetiracetam compared to phenytoin for seizure prophylaxis in adults with TBI. Hosp Pharm. 2013;48(9):757-761.
Kruer RM, et al. Changing trends in the use of seizure prophylaxis after TBI: A shift from phenytoin to levetiracetam. J Crit Care. 2013;28(5).
Gabriel WM, Rowe AS. Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after TBI. Ann Pharmacother. 2014;48(11):1440-1444.
Khan SA, et al. Comparison of efficacy of phenytoin and levetiracetam for prevention of early post traumatic seizures. J Ayub Med Coll Abbottabad. 2016;28(3):455-460.