Levetiracetam (Keppra) and Hyperammonemia
Levetiracetam (Keppra) is not known to cause hyperammonemia, unlike valproic acid which is well-documented to cause this adverse effect. 1
Evidence on Antiepileptic Drugs and Hyperammonemia
Medications Known to Cause Hyperammonemia
According to the clinical policy guidelines from the Annals of Emergency Medicine, valproate is specifically listed as causing hyperammonemia as an adverse effect 1. The table of antiepileptic medications in this guideline clearly identifies:
- Valproate: Associated with "dizziness, thrombocytopenia, liver toxicity, hyperammonemia"
- Levetiracetam (Keppra): Only associated with "nausea, rash"
Definition and Clinical Significance of Hyperammonemia
Hyperammonemia is defined as ammonia levels:
100 µmol/L (170 µg/dL) in neonates
- ≥50 µmol/L (85 µg/dL) in term infants, children, and adolescents 1, 2
Elevated ammonia levels can lead to serious neurological consequences including:
- Lethargy and loss of appetite
- Hyperventilation resulting in respiratory alkalosis
- Hypotonia, ataxia, disorientation
- Seizures
- Coma and death if untreated 1
Valproate-Induced Hyperammonemia
Multiple studies have documented valproate's association with hyperammonemia:
- Frequency of hyperammonemia with valproate therapy is approximately 27.8% 3
- Severe hyperammonemia (>150 µg/dL) occurs in about 5.1% of patients on valproate 3
- Risk increases with higher valproate dosage and plasma concentration 3
- Can occur even with normal liver function tests 4, 5
- Combination with other medications like topiramate may increase the risk 6
Levetiracetam as an Alternative
When comparing antiepileptic drugs in a study of patients undergoing craniotomy, researchers found:
- 80.95% of patients using valproate developed hyperammonemia
- Levetiracetam was not associated with hyperammonemia 7
In fact, levetiracetam has been successfully used as an alternative treatment in patients who developed hyperammonemia while on valproate therapy 6.
Clinical Implications
Monitoring Recommendations
- For patients on valproate who develop unexplained mental status changes, check ammonia levels
- Routine ammonia monitoring is not necessary for patients on levetiracetam alone
- Be particularly vigilant when using combinations of antiepileptic drugs
Treatment Considerations
- If hyperammonemia develops in a patient on multiple antiepileptic drugs including valproate, consider switching to levetiracetam
- Levetiracetam may be a safer option for patients with liver disease or urea cycle disorders who are at higher risk for hyperammonemia
Conclusion
While valproic acid is a well-documented cause of hyperammonemia (even with normal liver function), levetiracetam (Keppra) does not carry this risk based on current evidence and clinical guidelines.