Valproate-induced coma: case report and literature review

Ann Pharmacother. 1993 May;27(5):582-3. doi: 10.1177/106002809302700510.


Objective: To report a case of hyperammonemia without hepatic dysfunction as a possible cause of lethargy, stupor, and coma in a woman after valproic acid (VPA) administration, and discuss the possible different mechanisms of ammonia elevation and coma.

Case summary: A woman diagnosed with complex partial seizures that secondarily generalize was treated with phenytoin (PHT) 250 mg/d for 18 years. Three months before admission, this dosage was increased to 300 mg/d and phenobarbital (PB) 100 mg/d was added because the seizures were incompletely controlled. The patient developed a progressive inability to walk. She was diagnosed as having PHT intoxication. VPA therapy was begun while PHT was being tapered and progressive impairment of consciousness occurred. This evolved into a coma without focal neurologic signs, and was accompanied by isolated hyperammonemia without hepatic failure.

Discussion: Adverse effects attributable to VPA were reviewed in the literature. Occasionally, VPA may lead to severe secondary effects such as hepatic failure and coma. In these cases increased blood concentrations of transaminases, bilirubin, and ammonia have been found. Several reports have stressed the existence of hyperammonemic coma without biochemical evidence of hepatic failure, which is what occurred in our patient. This suggests that isolated hyperammonemia and hepatic failure after VPA treatment may have a different biochemical basis.

Conclusions: VPA-induced coma with hyperammonemia and without evidence of hepatic failure should be considered in patients being treated with PHT or PB when VPA is administered concomitantly. This case report shows the importance of clinical monitoring and immediate drug discontinuation when drowsiness, gastrointestinal symptoms, or lethargy occur.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Ammonia / blood*
  • Coma / chemically induced*
  • Epilepsy, Complex Partial / drug therapy
  • Female
  • Humans
  • Middle Aged
  • Phenobarbital / therapeutic use
  • Phenytoin / therapeutic use
  • Valproic Acid / administration & dosage
  • Valproic Acid / adverse effects*


  • Valproic Acid
  • Phenytoin
  • Ammonia
  • Phenobarbital