Post-Traumatic Seizure Prophylaxis in Patients with Traumatic Brain Injury Clinical Practice Guideline
Original Date: 08/2005 | Supersedes: 05/2017 | Last Review Date: 12/2020
Purpose: To standardize the delivery of post-traumatic seizure prophylaxis in patients with traumatic brain injury.
Recommendations
Patients with traumatic brain injury should receive 7 days of post-traumatic seizure prophylaxis (levetiracetam or phenytoin). (GRADE Level of Quality – moderate; USPSTF strength of recommendation – B [intervention is recommended])
Anti-Epileptic Drugs and Doses
Phenytoin (Dilantin®)/Fosphenytoin (Cerebyx®):
- Loading dose:
- Fosphenytoin 15 mg/kg (rounded to nearest 50 mg)
- Administered over 150 mg/min (e.g. 1g load given over 7 minutes)
- Fosphenytoin 15 mg/kg (rounded to nearest 50 mg)
- Maintenance dose:
Weight Phenytoin Phenytoin extended release <80 kg 100 mg PO/IV q 8 hours 300 mg PO qHS 80 – 110 kg 150 mg PO/IV q 8 hours 400 mg PO qHS >110 kg Consult pharmacy Consult pharmacy - Total phenytoin duration (IV and PO) is 7 days post-injury
- Enteral tube feeds impair the absorption of phenytoin capsules by up to 70%, so tube feeds should be held for 2 hours before and after
- Extended release phenytoin should not be crushed and put down an enteral feeding tube as this may affect the extended release
Levetiracetam (Keppra®):
- Loading dose:
- 1g IV once
- Maintenance dose:
- 1g PO/IV q12 hours x 7 days post-injury
- Levetiracetam pills can be crushed and put down enteral feeding tubes without a disruption in the delivery of tube
- 1g PO/IV q12 hours x 7 days post-injury
Background
In 1990, Temkin reported that phenytoin reduced the rate of early post-traumatic seizures from 14.2% to 3.6%. 1 Though no studies have shown the prevention of early post-traumatic seizures to be associated with improved survival or neurologic outcome, the potential benefits to preventing early post-traumatic seizures are thought to include preventing the development of chronic epilepsy, decreasing derangement in acute physiology, and preventing herniation.2
The use of levetiracetam for post-traumatic seizure prophylaxis has been increasing, presumably due to the well described side-effect profile of phenytoin including cutaneous hypersensitivity reactions, induction of the hepatic cytochrome P450 system, and drug-drug interactions.
Relevant Literature Search:
Despite the increasing use of levetiracetam, there has been no large, prospective, randomized controlled trial comparing the effectiveness of levetiracetam to phenytoin though there have been prospective observational and small randomized clinical trials.
Below are the results of a limited search for studies comparing phenytoin and levetiracetam including: randomized clinical trials, prospective observational studies, and prospective observational studies using a historical control group. The search was limited as there are a number of systematic reviews published within the past decade, which were used to ensure no relevant study was missed. For details of the search strategy, please see Appendix A.
| Author/Year | Study Type | Patients, n | Inclusion Criteria | Exclusion Criteria | Dosage | Outcomes |
|---|---|---|---|---|---|---|
| Szaflarski, 20103 | RCT (2:1 LEV >to PHE) | 52 (18 PHE, 34 LEV) | Severe TBI, SBP >90 mmHg, Age ≥17 years | No venous access, SCI, history of TBI, hemodynamic instability, anoxic injury, liver failure | PHE: 20mg/kg fos-PHE load, then 5mg/kg/day divided q12 hours (levels followed) LEV: 20mg/kg IV load, then 1g IV q12 hours | Early Post-Traumatic Seizures PHE – 5/18 (17%) LEV – 7/34 (15%) |
| Note: in the above study, all patients were monitored with continuous EEG for 72 hours or until awake and following commands to identify subclinical seizures. | ||||||
| Khan, 20164 | RCT (1:1 LEV to PHE) | 154 (77 PHE, 77 LEV) | Moderate or severe TBI and age 5-50 years | History of prior sz, delayed presentation >12h, renal or electrolyte derangements, pts undergoing surgery, pts who died within 7d | PHE: 20 mg/kg PHE load, then 5 mg/kg/d divided Q12H (serum levels not measured) LEV: 20 mg/kg LEV load, then 10-20 mg/kg divided Q12H |
Early Post-Traumatic Seizures PHE – 4/77 (5.2%) LEV – 7/77 (7.1%) |
| Note: the above study is at moderate to high risk for bias due to absence of PHE serum level monitoring, absence of continuous EEG, lack of blinding, and unclear randomization/allocation technique |
||||||
| Inaba, 20135 | Prospective observational | 813 (407 PHE, 406 LEV) | Blunt TBI Age ≥18 years | Pregnancy, non-survivable TBI, prehospital AED use, seizure before enrollment | PHE: 20mg/kg IV load, then 5mg/kg/day divided q8 hours (levels followed) LEV: 1g IV q12 hours |
Early Post-Traumatic Seizures PHE – 6/407 (1.5%) LEV – 6/406 (1.5%) |
| Note: in the above two center study, the majority of PHE patients were clustered at one center (396/407) and the majority of LEV patients were clustered at the other (329/406). | ||||||
| Jones, 20086 | Prospective observational (LEV) compared to historical control (PHE) | 73 (PHE 41, 32 LEV) | Severe TBI | Not stated | PHE: unclear LEV: 500mg IV q12 hours |
Early Post-Traumatic Seizures PHE – 0/41 (0%) LEV – 1/32 (3%) Abnormal EEG Findings PHE – 0/32 (0%) LEV – 8/42 (19%) |
| Note: in the above study, EEG were performed as needed – 15/32 LEV patients underwent 19 EEG and 12/41 PHE patients underwent 19 EEGs. | ||||||
Forest plot of the three included studies for the outcome: early post-traumatic seizures.
Cost Considerations:
Multiple studies have addressed the issue of cost associated with levetiracetam.7,8
However, there has recently been a reduction in the cost of levetiracetam have alleviated. The overall cost of multiple treatment strategies are delineated below:
| Treatment Strategy | Load | Maintenance | Total Cost |
|---|---|---|---|
| 1 | 1g fosphenytoin | phenytoin 100mg IV q8° x 7 days | $X |
| 2 | 1g levetiracetam | levetiracetam 1g IV q12 x 7 days | $0.95X |
| 3 | 1g levetiracetam | levetiracetam 1g IV q12 x 3 days levetiracetam 1g PO tab q12 x 4 days |
$0.77X |
| 4 | 1g levetiracetam | levetiracetam 1g IV q12 x 3 days levetiracetam 1g PO suspension q12 x 4 days |
$1.10X |
| 5 | 1g phenytoin | phenytoin 100mg IV q8° x 7 days | $0.22X |
Actual costs cannot be displayed. However, the costs of different regimens are provided in the form of multiples of the cost of fosphenytoin load followed by 7 days of IV phenytoin.
Appendix A: Search Strategy
As there are a number of recent systematic reviews regarding this topic, a more limited search was performed and the multiple systematic reviews were used to ensure that no relevant article was missed. Search limitations included: English language, randomized clinical trial, and prospective observational study (with or without historical control).
| Search | Database | Search Term | Limits | Total Yield: # of Articles | # Excluded Articles | # Included Articles |
|---|---|---|---|---|---|---|
| 1 | PubMed | phenytoin AND levetiracetam AND traumatic brain injury | Clinical Trial | 4 | 1 (LEV not compared to PHE) | 1 Prospective observational, 2 RCT |
| 2 | PubMed | phenytoin AND levetiracetam AND traumatic brain injury | Randomized Controlled Trial | 3 | 0 | 1 Prospective observational, 2 RCT (all duplicates) |
| 3 | PubMed | phenytoin AND levetiracetam AND traumatic brain injury | Systematic Review | 9 | 1 (outcome late post-traumatic seizure); 1 (LEV compared to placebo or no Tx); |
7 |
| total | 16 | 3 | 10 | |||
| Exclude Multiples 3 | ||||||
| Included Papers 10 (2 RCTs, 1 Observational, 7 SRs) | ||||||
Systematic Reviews evaluated:
- Khan NR, et al. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis. Dec 2016;79(6):775-82
- Yang Y, et Levetiracetam Versus Phenytoin for Seizure Prophylaxis Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis. CNS Drugs. Aug 2016;30(8):677-88
- Xu JC, et al. The Safety and Efficacy of Levetiracetam Versus Phenytoin for Seizure Prophylaxis after Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Brain 2016;30(9):1054-61
- Thompson K, et Pharmacological Treatments for Preventing Epilepsy
Following Traumatic Head Injury. Cochrane Database Syst Rev. Aug 2015;(8):CD009900 - Zafar SN, et Phenytoin versus Levetiracetam for Seizure Prophylaxis after Brain Injury – a meta analysis. BMC Neurol. May 2012;12:30
- Wilson CD, Burks JD, Rodgers RB, Evans RM, Bakare AA, Safavi-Abbasi S. Early and Late Posttraumatic Epilepsy in the Setting of Traumatic Brain Injury: A Meta-analysis and Review of Antiepileptic Management. World Neurosurg. 2018 Feb;110:e901-e906. doi: 1016/j.wneu.2017.11.116. Epub 2017 Dec 2. PMID: 29196247.
- Zhao L, Wu YP, Qi JL, Liu YQ, Zhang K, Li WL. Efficacy of levetiracetam compared with phenytoin in prevention of seizures in brain injured patients: A meta-analysis. Medicine (Baltimore). 2018 Nov;97(48):e13247. doi: 1097/MD.0000000000013247. PMID: 30508910; PMCID: PMC6283080.
Review of the systematic reviews failed to identify a missed randomized clinical trial, prospective observational study, or prospective observational study using a historical control.
References
1 Temkin NR, et al. A Randomized, Double-Blind Study of Phenytoin for the Prevention of Post-Traumatic Seizures. N Engl J Med. Aug 1990;323(8):497-502
2 Guidelines for the Management of Severe Traumatic Brain Injury, 4th Edition. https://braintrauma.org/uploads/03/12/Guidelines_for_Management_of_Severe_TBI_4th_Edition.pdf
3 Szaflarski JP, et al. Prospective, Randomized Single-Blinded Comparative Trial of Intravenous Levetiracetam Versus Phenytoin for Seizure Prophylaxis. Neurocrit Care. Apr 2010;12(2):165-72.
4 Khan SA, Bhatti SN, Khan AA, Khan Afridi EA, Muhammad G, Gul N, Zadran KK, Alam S, Aurangzeb A. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016 Jul-Sep;28(3):455-460. PMID: 28712212.
5 Inaba K, et al. A Prospective Multicenter Comparison of Levetiracetam versus Phenytoin for Early Post-Traumatic Seizure Prophylaxis. J Trauma Acute Care Surg. Mar 2013;74(3):766-71.
6 Jones KE, et al. Levetiracetam Versus Phenytoin for Seizure Prophylaxis in Severe Traumatic Brain Injury. Neurosurg Focus. Oct 2008;25(4):E3
7 Cotton BA, et al. Cost-Utility Analysis of Levetiracetam and Phenytoin for Post-Traumatic Seizure Prophylaxis. J Trauma. Aug 2011;71(2):375-9
8 Pieracci FM, et al. A Cost-Minimization Analysis of Phenytoin Versus Levetiracetam for Early Seizure Pharmacoprophylaxis after Traumatic Brain Injury. J Trauma Acute Care Surge. Jan 2012;72(1):276-81