How to prevent and manage hyperammonemic encephalopathies in valproate therapy

Abstract Background Valproic acid (VPA) has been increasingly shown to trigger hyperammonemic encephalopathies in patients suffering from urea cycle defects and in those receiving polypharmacy. Methods We report on two cases of psychiatric inpatients with regular VPA intake who showed severe cognitive impairment due to non-cirrhotic hyperammonaemia without VPA overdosing. Results In the first case, OTC deficiency appeared to be the underlying cause of a comatose state in a middle-aged bipolar female patient. Besides hyperammonemia, we identified increased plasma levels of glutamine and alanine, decreased plasma levels of arginine and urea, as well as increased urinary levels of orotate. In the second case, we observed severe cognitive impairment in a younger male patient with a current psychotic episode with predominant affective symptoms who we treated with polypharmacy including VPA and topiramate. Limitations As this case series focused on individual patients, the results should be interpreted with caution and cannot be generalized. Conclusions In patients receiving VPA, considering urea cycle deficiencies and potential drug interactions seems crucial for avoiding potential life-threatening symptoms.