The reported incidence of hyperammonemia in children in monotherapy with valproate is 19%, although the incidence of encephalopathy due to treatment with valproate is not well known. The appearance of hyperammonemia is not dose-dependent, and may occur in patients with normal doses and levels of valproic acid. Sometimes hyperammonemia is associated with the development of encephalopathic symptoms (while liver function tests remain normal) that reverse with discontinuation of the drug, therefore proper detection and diagnosis is important .

From my clinical experience, hyperammonemia is not that frequent with sodium or magnesium valproate up to 1500mg/2000mg day in healthy adults receiving monotherapy, especially for the acute management of mania. In case of epilepsy it may be used up to 3gr/day but the risks for toxicity do increase proportionally. So, from my own experience with patients IT IS (!!!!) largely dose dependent. Hyperammonemia may cause central hyponatremia and could be associated with cognitive and cardiological toxicity. Also bare in mind that a major metabolism pathway for the drug is UGT and CYP2C9 and CYP2C19: although you may exclude in most of the cases any clinically relevant pharmacokinetic interaction which could RISE the levels of valproate (on the opposite side, valproate may INDUCE CYP3A4 substrates including lamotrigine, but this is an another story), in some cases valproate could rise the pancreatic functioning (a specific parameter is represented by the pancreatic lipase), so you could monitor it too. Most importantly, the clearance pathway for valproate is the GI, not just the urinary trait, and that patients with severe constipation may be at higher risk to reach toxic levels of valproatemia (which you could monitor by blood sampling). A rapid and effective way to manage valproate intoxication (including: fever, hypothermia, hypotension, cardiac arrest and respiratory depression) is represented by the withdrawal (sudden w. if fine in case of acute toxicity) plus the administration L-carnitine, which is very important in case of life-threatening valproate intoxication. But apart from specific cases (e.g. PCOS in fertile women) or specific pancreatic conditions, I find valproate a cornerstone treatment for a number of mood disorders, so I always use it with confidence and I many patients (including bipolar I and II and/or epileptic ones) who tolerate 2000 or even 2250mg/day since years. I rarely go beyond such doses, and I prefer reducing valproate to add a second agent (including SGAs or lithium) to enhance both safety, efficacy and long-term tolerability.

To sum-up: hyperammoniemia may lead to both toxic encephalitis and permanent damages to liver, kidney and pulmonary functions. USE valproate with confidence BUT if you really suspect toxicity is occurring (valproatemia may help), suddendly remove it and introduce creatine/L-carnitine which counterbalances the effects of ammonia.

Michele.

Adding L-carnitine can address delirium due to valproate toxicity. I have treated two hospitalized patients who were developed delirium while taking valproate. The L-carnitine resolved the delirium within three days for each patient. This solution won't help the patient who is delirious from other causes, however.

I agree with Bruce Capehart.

Lactulose 10G/15ml once or twice daily, according to the patient's tolerance can be used for treatment of hepatic encephalopathy from valproate.  Monitor for potential dehydration, hypokalemia and hyponatremia as well as ammonia until in the normal range. This would be the case for milder forms of hyperammonemia and no evidence of other signs of valproate intoxication such as fever, hypothermia, hypotension, EKG changes or cardiac arrest, and respiratory depression mentioned by Dr. Fornaro. But as Dr. Fornaro and Dr. Lopez suggest, abrupt discontinuation of valproate would be the best.  Thank you doctors for the information about L-carnitine.  Larry Berley