COMMENT. VPA toxicity, particularly hepatotoxicity, in infants and young children may be reduced in frequency by elimination of concurrent anticonvulsants, but serum ammonia must be closely monitored even with monotherapy. Cerebral edema, increased intracranial pressure, cytotoxic changes in the brain and coma are reported with hyperammonemia exceeding 500 umol/1 in neonates, and intellectual retardation and brain damage are correlated with duration of hyperammonemia and coma [2]. Animal experiments show that VPA-induced hyperammonemia is caused primarily by impairment of hepatic intramitochondrial citrullinogenesis, and the renal contribution to systemic hyperammonemia is small. [3]

Brown JK, at the Royal Hospital for Sick Children, Edinburgh, writing on valproate toxicity in Developmental Medicine and Child Neurology [4], cautions that any congenital inborn error of metabolism that affects mitochondrial function or any acquired mitochondriopathy might be expected to increase the risk of serious valproate toxicity in the neonate, and VPA is not generally recommended in the newborn period. He stresses the need for detailed investigation of cases of hepatopathy, including a full screen of mitochondrial enzyme function, as well as histology for possibly Reye-type changes, before accepting a diagnosis of VPA-induced hepatotoxicity.