Treatment of encephalopathy by means of valproic acid with carglumic acid: two case reports and a review of the literature

Valproic acid (VPA) is a drug mainly used to treat epilepsy. Hyperammonaemic encephalopathy due to VPA is a rare but serious complication. The mechanism by which VPA influences the increase in ammonia consists in blocking the urea cycle, thereby inhibiting N-acetylglutamate synthase and diminishing acetyl coenzyme A. Generally, the treatment employed has been to withdraw VPA and to administer arginine, carnitine, antibiotics, glucose and protein restriction. Previous experience with carglumic acid is limited to reports of isolated cases of paediatric patients. We report the cases of two adult patients with encephalopathy due to VPA who were treated with carglumic acid, in addition to the conventional measures. Following treatment with the drug, ammonia levels can be seen to return to normal values. In one of the two cases, owing to the existence of another cause of encephalopathy, no clinical improvement was observed. From the biochemical point of view, treating encephalopathy due to VPA with carglumic acid is a logical step, as it reverses the blockage of the urea cycle conditioned by VPA. The mechanism proposed as being the one by which brain toxicity and, therefore, encephalopathy are produced is the passage of ammonia in the form of glutamine to the inside of the cell, which then returns to ammonia and glutamate in the mitochondria and leads to oxidative stress. Carglumic acid must be considered an important part of the treatment in adult patients with hyperammonaemic encephalopathy due to VPA, although a randomised clinical trial needs to be conducted with the drug in order to test its efficacy.