What is the recommended antiepileptic protocol in patients with neurotrauma?

Antiepileptic Protocol in Neurotrauma

Primary Recommendation

For early post-traumatic seizure prophylaxis (first 7 days after traumatic brain injury), administer either levetiracetam or phenytoin/fosphenytoin, with levetiracetam preferred due to superior tolerability and fewer drug interactions. 1, 2

Indications for Seizure Prophylaxis

Antiepileptic prophylaxis should be initiated in patients with:

• Severe traumatic brain injury (TBI) with Glasgow Coma Scale ≤8 2
• Intracranial hemorrhage (subdural, epidural, or intracerebral) 3, 1
• Depressed skull fracture 3
• Penetrating brain injury 2
• Loss of consciousness or amnesia >24 hours 3
• Age >65 years with TBI 3

First-Line Agent Selection

Levetiracetam (Preferred)

• Dosing: 1000-1500 mg IV loading dose, then 500-1500 mg twice daily 1, 2
• Advantages: Better tolerability profile, no significant drug interactions, no need for serum level monitoring 1, 2
• Caution: Standard loading doses may not achieve therapeutic CSF levels immediately; higher doses may be needed in acute settings 4

Phenytoin/Fosphenytoin (Alternative)

• Dosing: 18-20 mg/kg IV (or PE/kg for fosphenytoin) at maximum rate of 50 mg/min for phenytoin or 150 PE/min for fosphenytoin 5
• Advantages: Extensively studied, reaches therapeutic CSF levels more reliably when weight-based dosing approximates fixed dosing 4, 2
• Disadvantages: Hypotension risk (12% incidence), requires cardiac monitoring during infusion, significant drug interactions, requires serum level monitoring 5
• Fosphenytoin causes fewer infusion-related adverse events than phenytoin in head-to-head comparisons 5

Valproate (Alternative)

• Dosing: 20-30 mg/kg IV at maximum rate of 10 mg/kg/min 5
• Efficacy: Comparable to phenytoin (88% vs 84% seizure control in refractory status epilepticus) 5
• Major concern: Associated with increased mortality in some TBI studies; use with caution 2

Duration of Prophylaxis

Discontinue prophylactic antiepileptic therapy after 7 days post-injury. 1, 2

• Early seizures (within 7 days) occur in approximately 2.2% of all TBI cases, but up to 38% in severe TBI with acute subdural hematoma 3, 1
• Prophylaxis beyond 7 days does not prevent late post-traumatic seizures (>7 days) or post-traumatic epilepsy 2
• Long-term prophylaxis may worsen cognitive outcomes and is not recommended 1

Management of Active Seizures in Neurotrauma

First-Line Treatment

• Benzodiazepines (lorazepam preferred) for immediate seizure termination 5

Second-Line Treatment for Refractory Status Epilepticus

If seizures persist after benzodiazepines, the 2024 ACEP guidelines and ESETT trial demonstrate equal efficacy among:

• Levetiracetam 60 mg/kg IV (maximum 4500 mg) over 10 minutes: 47% seizure cessation 5
• Fosphenytoin 20 PE/kg IV over 10 minutes: 45% seizure cessation 5
• Valproate 40 mg/kg IV (maximum 3000 mg) over 10 minutes: 46% seizure cessation 5

The ESETT trial found no significant difference in efficacy among these three agents, so selection should be based on side effect profile and patient-specific factors. 5

Third-Line Options

For continued refractory status epilepticus:

• Propofol, barbiturates, or midazolam infusions 5

Critical Monitoring Considerations

• Continuous EEG monitoring should be considered in patients with depressed mental status disproportionate to brain injury severity to detect nonconvulsive seizures 3, 1
• Head CT is the preferred initial imaging modality to identify acute intracranial hemorrhage or mass effect requiring urgent intervention (100% sensitivity for acutely treatable lesions) 3, 1
• Serial neurological examinations are essential, as high-dose antiepileptics may confound clinical assessment and prognostication 5

Important Caveats and Pitfalls

Avoid phenobarbital and carbamazepine for TBI seizure prophylaxis—no demonstrated advantage over phenytoin with worse adverse effect profiles. 2

Do not use high-dose glucocorticoids after severe TBI (Brain Trauma Foundation Grade 1- recommendation). 6

Recognize that myoclonic seizures may represent Lance-Adams syndrome, which is compatible with good outcomes; overly aggressive treatment may not be warranted. 5

In post-cardiac arrest patients with TBI, routine seizure prophylaxis is not recommended, but active seizures should be treated. 5

Levetiracetam at standard dosing (500-1000 mg) may not reach therapeutic CSF levels in the acute setting; consider higher loading doses (1500 mg) for immediate neuroprotection. 4

The presence of early seizures does not reliably predict late post-traumatic epilepsy in multivariate analyses. 3