Valproic Acid

GENERAL PRINCIPLES

Pathophysiology

• Valproic acid (VPA) is widely prescribed for the management of seizures and mood disorders. It exerts its effects in therapeutic dose and overdose by inhibiting the function of voltage-gated sodium and calcium channels as well as enhancing the function of GABA.

• VPA is metabolized by the hepatocytes through a complicated biochemical process that involves #946;- oxidation in the mitochondria.

o VPA may produce profound DILI in overdose or therapeutic use. DILI due to VPA is characterized by microvesicular steatosis.

î VPA metabolism may lead to significant ammonia accumulation (ammonia concentrations gt;80 #956;g#8725;dL or gt;35 #956;mol#8725;L), leading to profound encephalopathy, a condition called valproate-induced hyperammonemic encephalopathy (VHE). Many patients taking VPA may have mild ammonia elevations without systemic symptoms.

DIAGNOSIS

Clinical Presentation

• Patients with valproate poisoning may present with tremor, ataxia, sedation, altered sensorium, or coma.

• Patients with DILI due to VPA may complain of abdominal pain or present with jaundice or hepatic encephalopathy.

• Patients with VHE will typically be profoundly encephalopathic or comatose.

Differential Diagnosis

• Valproate poisoning is similar to poisoning by other anticonvulsants. Patients with carbamazepine poisoning typically exhibit antimuscarinic signs and/or cardiotoxicity, which are not seen in valproate poisoning.

• The nontoxicologic differential diagnosis for valproate poisoning should include Wernicke encephalopathy, meningoencephalitis, posterior circulation ischemic stroke, and intracranial hemorrhage and mass lesion.

• Other causes of hyperammonemia such as hepatic encephalopathy and inborn errors of metabolism should be considered.

Diagnostic Testing

LABORATORIES

• Obtain a valproate concentration.

• Obtain a complete metabolic panel to assess for evidence of metabolic acidosis or hepatic injury.

• Obtain a complete blood count, as valproate poisoning has been associated with pancytopenia.

• Obtain an ammonia concentration.

î Markedly elevated ammonia levels in a patient with encephalopathy or coma may suggest VHE. î Do not be alarmed by mild ammonia elevations in asymptomatic or minimally symptomatic patients.

TREATMENT

• Most patients will do well with cessation of valproate therapy and supportive care.

• Treat seizures with benzodiazepines or other directly GABAergic agents.

• Patients with VHE may benefit from levocarnitine therapy.

î In patients who are critically ill (most hospitalized patients with VHE), levocarnitine should be administered IV: 100 mg/kg (up to 6 g) as a loading dose, followed by 15 mg/kg every 4 hours.

î Levocarnitine therapy may be discontinued when the ammonia level has normalized and the patient is clinically improving.

• Therapy with lactulose, which is routinely used for the treatment of hepatic encephalopathy in cirrhosis, is not thought to be effective in VHE.

• Hemodialysis effectively clears valproate.

î Hemodialysis is recommended in severe VPA poisoning when [VPA] is gt;1300 mg/L or when shock or cerebral edema is present.

î Hemodialysis is suggested in severe VPA poisoning when [VPA] is gt;900 mg/L, coma or respiratory depression requiring mechanical ventilation is present, acute hyperammonemia is present, or the pH is lt;7.10. ¹²