From the FDA Drug Label
In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy
The antiepileptic medication most likely to cause encephalopathy is valproic acid when used in combination with topiramate. The provided information does not specify which antiepileptic medications are least likely to cause encephalopathy and triphasic waves. Key points:
- Concomitant administration of valproic acid and topiramate is associated with hyperammonemia with and without encephalopathy.
- No information is provided about the likelihood of other antiepileptic medications causing encephalopathy and triphasic waves. 1
From the Research
Valproic acid is the antiepileptic medication most likely to cause encephalopathy and triphasic waves, while levetiracetam is least likely to cause these adverse effects. The association between valproic acid and encephalopathy is well-documented, with the medication inducing hyperammonemia, particularly in patients with underlying urea cycle disorders or liver dysfunction, leading to metabolic encephalopathy characterized by altered mental status, confusion, and triphasic waves on EEG 2. Other antiepileptic drugs that commonly cause encephalopathy include phenytoin, carbamazepine, and phenobarbital, especially at supratherapeutic levels or when used in combination therapy, impairing neuronal function through various mechanisms including GABA potentiation, sodium channel blockade, and glutamate inhibition 3. Newer generation antiepileptics like levetiracetam, lamotrigine, and lacosamide have a lower risk of encephalopathy due to their more selective mechanisms of action and favorable pharmacokinetic profiles 4. Some studies have also reported that other medications, such as pregabalin, can cause encephalopathy and triphasic waves, especially in patients with renal insufficiency 5. Additionally, cefepime has been associated with encephalopathy and triphasic waves, particularly in patients with preexisting white matter disease or renal impairment 6. When prescribing valproic acid, regular monitoring of ammonia levels, liver function tests, and clinical assessment for signs of encephalopathy is essential, particularly during dose adjustments or when adding interacting medications. Patients with risk factors such as polypharmacy, advanced age, or hepatic impairment require especially careful monitoring. Key points to consider when evaluating the risk of encephalopathy and triphasic waves in patients taking antiepileptic medications include:
- The specific medication being used, with valproic acid being the most likely to cause encephalopathy and triphasic waves
- The patient's underlying medical conditions, such as liver dysfunction or urea cycle disorders
- The presence of risk factors, such as polypharmacy, advanced age, or hepatic impairment
- The need for regular monitoring of ammonia levels, liver function tests, and clinical assessment for signs of encephalopathy.