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.
  • 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 the incidence of early seizures but have not been shown to prevent later development of epilepsy.
  • Prevention of early seizures is beneficial in order to prevent status epilepticus, which further aggravates systemic injury.
  • The 2016 Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury; however, levetiracetam is commonly used in this setting. A 2024 Neurocritical Care Society guideline has since offered a weak recommendation favoring levetiracetam over phenytoin/fosphenytoin — see Guideline Recommendation below.

Clinical Detail

Pharmacology

PhenytoinValproic AcidLevetiracetamLacosamide
DoseLoading dose: 17–20 mg/kg IV (max dose 2 g)
Maintenance dose: 100 mg every 8 hours or 5 mg/kg/day divided q8h (individual doses not to exceed 400 mg)
Duration not to exceed 7 days		10–15 mg/kg/dayLoading dose: 20 mg/kg IV infused over 5–20 min
Maintenance dose: 1 g IV over 15 min every 12 hours for 7 days (may be increased to 1.5 g q12h)		50–100 mg IV twice daily
May give loading dose of 200 mg
AdministrationIV piggyback rate of ≤50 mg/minuteIV piggyback over 60 minutes at a rate ≤20 mg/minuteIV push or piggyback over 5–20 minBolus: may be administered undiluted at ≤80 mg/minute
Infusion: over 30 to 60 minutes
PK/PDOnset: 30 min–1 hour
Half-life: 10–12 hours		Peak: <1 hour
Half-life: 9–19 hours		Peak: 5–30 minutes
Half-life: 6–8 hours		Peak: <1 hour
Half-life: ~13 hours
Adverse EffectsHematologic effects, cardiovascular effects, CNS effects, gingival hyperplasia, hepatotoxicityCNS effects, hematologic effects, hepatotoxicity, encephalopathy, pancreatitisCNS depression, hypersensitivity reactions, psychiatric and behavioral abnormalities, increased blood pressure, astheniaCardiac arrhythmias including bradycardia and AV block, CNS effects
WarningsVesicant, acute toxicityNot recommended for post-traumatic seizure prophylaxis in patients with acute head traumaCaution in renal impairmentAdminister loading doses under medical supervision due to increased incidence of CNS adverse reactions

Guideline Recommendation

GuidelineRecommendation
Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition — Brain Trauma Foundation, 2016/20172
  • Phenytoin is recommended to decrease the incidence of early post-traumatic seizures (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.
Updated Guideline (2024)
Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate–Severe TBI — Neurocritical Care Society (Frontera et al.), 202415
  • Antiseizure medication (ASM) or no ASM may be used (weak recommendation, low-quality evidence) — the systematic review found no significant effect on early seizure, late seizure, adverse events, or mortality.
  • If an ASM is used, levetiracetam is suggested over phenytoin/fosphenytoin (weak recommendation, very-low-quality evidence) — point estimates favored levetiracetam for fewer late seizures and adverse events, but differences were not statistically significant.
  • Short-term use of ≤ 7 days is recommended (weak recommendation, low-quality evidence) — longer durations showed worse cognitive outcomes and more adverse events without reducing seizure incidence.

The 2024 Neurocritical Care Society guideline supersedes the 2016/2017 Brain Trauma Foundation guideline as the most current formal recommendation on drug choice; both are shown for context since the BTF guideline remains widely cited in practice.

Evidence

Author, yearDesign / sample sizeIntervention & comparisonOutcome
Temkin et al., 1990Randomized, double-blind, placebo-controlled trial
N = 404		Phenytoin vs. placeboWithin the first week, 3.6% of phenytoin patients experienced seizure vs. 14.2% of placebo patients (P<0.001). Between day 8 and 1 year, 21.5% of the phenytoin group vs. 15.7% of the placebo group experienced seizure (not significant). Phenytoin is effective in reducing seizures within the first 7 days after severe head injury but does not affect late seizure risk.
Young et al., 2004Randomized, double-blinded, placebo-controlled trial in pediatric patients (age <16 yo)
N = 102		Phenytoin vs. placebo for prevention of early posttraumatic seizuresDuring the 48-hour observation period, 3 of 46 (7%) phenytoin patients and 3 of 56 (5%) placebo patients experienced a posttraumatic seizure. No significant difference in survival or neurologic outcome. Phenytoin did not significantly reduce the rate of posttraumatic seizures at 48 hours, neurologic outcomes, or overall survival at 30 days in children.
Jones et al., 2008Prospective, single-center trial
N = 73 (32 levetiracetam, 41 phenytoin)		Phenytoin vs. levetiracetam in patients with severe TBI (GCS 3–8)Equivalent incidence of seizure activity between levetiracetam and phenytoin (P=0.556). Levetiracetam patients had a higher incidence of abnormal EEG findings (P=0.003). Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG.
Szaflarski/Sangha et al., 2010Prospective, single-center, randomized, single-blinded comparative trial
N = 52		Levetiracetam vs. phenytoin in patients with severe TBI or subarachnoid hemorrhageLevetiracetam patients experienced better long-term outcomes. No difference in seizure occurrence during continuous EEG (5/34 levetiracetam vs. 3/18 phenytoin; P=1.0), at 6 months (1/20 vs. 0/14; P=1.0), or mortality (14/34 vs. 4/18; P=0.227). Lower frequency of worsened neurological status (P=0.024) and GI problems (P=0.043) with levetiracetam; mortality was numerically higher with levetiracetam but not statistically significant. Levetiracetam improved long-term neurological outcomes compared to phenytoin with fewer ADRs and may be an alternative (mortality difference not significant).
Ma et al., 2010Retrospective cohort study
N = 159 (87 severe, 72 mild/moderate TBI)		Sodium valproate vs. no treatment for early posttraumatic seizuresNo patients who received sodium valproate experienced seizures; the study was not sufficiently powered to detect a statistically significant difference. Sodium valproate showed a favorable trend in decreasing early posttraumatic seizures, but the finding was not statistically significant.
Inaba et al., 2013Prospective, multicenter comparative study
1,191 screened; 813 analyzed (406 levetiracetam, 407 phenytoin)		Levetiracetam vs. phenytoin for prevention of early posttraumatic seizuresNo difference in seizure rate (1.5% vs. 1.5%; P=0.997). No difference between levetiracetam and phenytoin in the prevention of early posttraumatic seizures, mortality, or ADRs following TBI.
Caballero et al., 2013Multicenter retrospective analysis
N = 90 (18 levetiracetam, 72 phenytoin)		Phenytoin vs. levetiracetam in TBI with ≥1 day of EEG monitoringEEG-confirmed seizure activity similar between groups (28% vs. 29%; P=.99). Median daily cost: $43 (levetiracetam) vs. $55 (phenytoin) (P=.08). Levetiracetam may be an alternative for seizure prevention in ICU TBI patients while lowering drug and monitoring costs.
Kruer et al., 2013Retrospective observational study
N = 109 (89 phenytoin, 20 levetiracetam)		Phenytoin vs. levetiracetam in patients with TBI and GCS <81 of 89 phenytoin patients and 1 of 20 levetiracetam patients experienced a posttraumatic seizure. Only 2 patients total experienced a posttraumatic seizure, indicating a low overall incidence regardless of agent.
Gabriel & Rowe, 2014Single-center, prospective cohort analysis
N = 19		Phenytoin vs. levetiracetam after severe TBINo difference in Glasgow Outcome Scale–Extended score at ≥6 months. No difference in early (P=0.53) or late (P=0.53) seizures. More fever days in the phenytoin group. Long-term functional outcome was not affected by choice of phenytoin vs. levetiracetam.
Khan et al., 2016Randomized controlled trial
N = 154 (77 per group)		Phenytoin vs. levetiracetam in moderate-to-severe head traumaPhenytoin prevented early posttraumatic seizures in 73/77 (94.8%) patients; levetiracetam in 70/77 (90.9%) patients (not statistically significant). No significant difference in efficacy between phenytoin and levetiracetam.
Recent Evidence (2024–2026)
Karamian et al., 2024Systematic review & meta-analysis (16 studies: 3 RCT, 10 retrospective cohort, 3 prospective cohort)
N = 5,821		Levetiracetam vs. phenytoin for seizure prevention after TBINo difference in early seizure (OR 0.85; 95% CI 0.60–1.21), late seizure (OR 0.87; 95% CI 0.21–3.67), adverse events (OR 0.69; 95% CI 0.44–1.08), or mortality (OR 1.11; 95% CI 0.92–1.34). Levetiracetam shortened ICU length of stay (MD −2.25 days; 95% CI −3.58 to −0.91). Confirms equivalent seizure prevention with a possible ICU-stay advantage for levetiracetam.
Thorman et al., 2026Retrospective cohort, TriNetX real-world network
N = 51,263 (33,625 mild, 10,805 severe TBI, remainder moderate TBI; 14,630 received levetiracetam)		Levetiracetam prophylaxis, stratified by TBI severityLevetiracetam reduced early epilepsy (<7 days) in severe TBI (HR 0.55; 95% CI 0.31–0.97; P=0.04) but not in mild TBI (HR 0.85; 95% CI 0.45–1.61; P=0.61). No reduction in late epilepsy (<1 year) in either stratum. The early-seizure benefit of levetiracetam prophylaxis may be limited to more severe injury — a severity-stratified nuance not captured in the older trials above.
Onda et al., 2025Retrospective comparative study
N = 200 (55 perampanel, 145 levetiracetam)		Perampanel vs. levetiracetam for early seizure prophylaxis after severe TBIEarly posttraumatic seizure occurred in 1.8% of the perampanel group vs. 15.9% of the levetiracetam group (Firth-adjusted OR 0.158; 95% CI 0.017–0.644; P=0.007); perampanel also shortened mechanical ventilation duration. No adverse events reported in either group. Preliminary signal only — small, single-center, retrospective; not yet reflected in any guideline.

Conclusions

  • Phenytoin and levetiracetam show consistently equivalent efficacy for preventing early post-traumatic seizures across trials from 1990 through the 2024 meta-analysis (16 studies, n=5,821) — neither agent is clearly superior, and prophylaxis has never been shown to prevent later development of epilepsy.
  • The 2024 Neurocritical Care Society guideline gives a weak recommendation favoring levetiracetam over phenytoin/fosphenytoin, based on a trend toward fewer late seizures and adverse events (not statistically significant) plus a shorter ICU length of stay per the 2024 meta-analysis. This updates — but does not overturn — the older 2016/2017 Brain Trauma Foundation guideline, which still recommends phenytoin and found insufficient evidence to prefer levetiracetam.
  • Duration should be limited to ≤ 7 days per the 2024 guideline — longer prophylaxis has not shown additional seizure benefit and is associated with worse cognitive outcomes and more adverse events.
  • A 2026 severity-stratified real-world cohort (n=51,263) suggests the early-seizure benefit of levetiracetam may be concentrated in severe TBI (HR 0.55, P=0.04) and not present in mild TBI — a nuance not captured by the older, mostly severe-TBI-only trial population.
  • Valproic acid is not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma per drug labeling, despite a favorable but statistically non-significant signal in one small retrospective cohort.
  • Newer agents are being explored but neither is yet endorsed by a formal guideline: lacosamide is used off-label in this setting, has no head-to-head trial against phenytoin/levetiracetam in the trials above, and per its own pharmacology carries a distinct cardiac-conduction risk (bradycardia, AV block) not shared by levetiracetam or valproic acid; perampanel showed a large but preliminary reduction in early seizures vs. levetiracetam in a single small 2025 retrospective study (n=200) and needs prospective confirmation before it changes practice.

References

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  • Young KD, Okada PJ, Sokolove PE, 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. Annals of Emergency Medicine. 2004;43(4):435-446. doi:10.1016/j.annemergmed.2003.09.016
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Tags:traumatic brain injury seizure prophylaxis levetiracetam phenytoin