Can Valproate Be Added to Levetiracetam in Post-Traumatic Seizures?
No, valproate should not be added to levetiracetam for seizure prophylaxis in patients with post-traumatic seizures due to subdural hematoma, as routine antiepileptic prophylaxis is not recommended, and valproate specifically has been associated with increased mortality in traumatic brain injury patients.
Evidence Against Routine Antiepileptic Prophylaxis
The most recent guidelines explicitly recommend against using antiepileptic drugs for primary prevention of post-traumatic seizures 1. The 2018 Anaesthesia guidelines state that "prevention of post-traumatic seizures with AEDs cannot be recommended" based on analysis of 11 clinical trials involving over 2,700 patients 1.
- Multiple studies showed no significant effect of antiepileptic drugs in preventing early or delayed post-traumatic seizures 1
- Some studies demonstrated worsening neurological outcomes with antiepileptic prophylaxis 1
- Acute subdural hematoma is identified as a risk factor for delayed seizures, but this does not justify routine prophylaxis 1
Specific Concerns with Valproate
Valproate carries particularly concerning risks in traumatic brain injury patients and should be avoided:
- A randomized trial showed a trend toward higher mortality in valproate-treated patients (13.4%) compared to phenytoin (7.2%), with a relative risk of 2.0 2
- Valproate showed no benefit over short-term phenytoin for preventing early seizures and neither prevented late seizures 2
- The lack of additional benefit combined with potentially higher mortality suggests valproate should not be routinely used for post-traumatic seizure prevention 2
Drug Interaction Profile
From a pharmacokinetic standpoint, combining these medications is technically feasible but clinically unnecessary:
- Levetiracetam does not affect the glucuronidation of valproic acid 3
- Valproate 500 mg twice daily does not modify levetiracetam absorption, plasma clearance, or urinary excretion 3
- There is no effect on exposure to levetiracetam's primary metabolite when combined with valproate 3
When Antiepileptic Therapy May Be Considered
If seizure prophylaxis is deemed necessary due to specific high-risk features, levetiracetam monotherapy is preferred:
- Prophylaxis can be considered in cases with specific risk factors such as chronic subdural hematoma or past history of epilepsy 1
- When used, levetiracetam should be preferred to phenytoin due to higher degree of tolerance 1
- For status epilepticus refractory to benzodiazepines, levetiracetam, fosphenytoin, or valproate show similar efficacy (approximately 47% success rate), but this is for active seizure treatment, not prophylaxis 1
Risk Factors Specific to Your Patient
In the context of subdural hematoma, the seizure risk varies by type:
- Acute subdural hematoma carries a 28% incidence of early post-traumatic seizures and 43% incidence of late seizures over 2 years 4
- Risk factors in acute subdural hematoma include 24-hour postoperative GCS below 9, craniotomy, and preoperative GCS below 8 4
- Initial loss of consciousness or amnesia for more than 24 hours increases risk 1, 5
Common Pitfalls to Avoid
- Do not use valproate for traumatic brain injury prophylaxis given the mortality signal 2
- Avoid polypharmacy when monotherapy with levetiracetam (if indicated) would suffice 1
- Do not continue prophylactic antiepileptics long-term unless actual seizures occur 6
- If levetiracetam is used, ensure adequate dosing (>1000 mg total daily dose may be more effective than 1000 mg daily) 7
Monitoring Considerations
If levetiracetam is already being used and seizures occur despite therapy:
- This represents treatment failure, not an indication to add valproate 1
- Consider alternative second-line agents like fosphenytoin for breakthrough seizures 1
- Evaluate for underlying causes of seizures beyond the subdural hematoma 6
- Monitor for levetiracetam-associated adverse effects including behavioral changes and rare hepatotoxicity 8