Valproate Toxicity

Etiology

Valproate toxicity commonly occurs when ramping up the dose to achieve a therapeutic effect. Valproate toxicity may also occur when free or unbound drug levels become elevated. Elevated free drug concentrations are common in older patients and patients with hypoalbuminemia, and also in those who are pregnant, have renal dysfunction, liver disease, or in those who use medications that compete with valproate for albumin binding sites.[3] Additionally, patients who intentionally overdose on valproate during attempts of self harm experience varying degrees of valproate toxicity.[4]

Epidemiology

According to the American Association of Poison Control Centers' National Poison Data System, cases of acute ingestion of valproate increased from 2717 in 1994 to 8705 in 2005.[5] More recently, cases of acute ingestion of valproate cases have stabilized. There were 3211 cases of acute valproate ingestion in 2010 and 2996 cases in 2018.[6] Children may be at particular risk for valproate toxicity, though it can occur in patients of all ages.[7]

Pathophysiology

Patients with valproate toxicity commonly experience hyperammonemia, encephalopathy, and hepatotoxicity.[8] Valproate decreases tissue carnitine levels, which results in microvesicular steatosis and hyperammonemia.[9][10] Valproate-induced encephalopathy is typically related to the effects of hyperammonemia. However, valproate-induced cerebral edema may also be impacted by altered valproate metabolism, which allows the presence of toxic drug metabolites to enter the brain.[8][11] Valproate-induced hepatotoxicity is likely due to inhibiting beta-oxidation of fatty acids, which results in mitochondrial injury.

Toxicokinetics

In the United States, oral valproate formulations include valproic acid, sodium valproate, and divalproex. Valproic acid and sodium valproate are immediate-release formulations, while divalproex is formulated as delayed- or extended-release. Valproate is also formulated for intravenous use as sodium valproate.[12] The liver metabolizes valproate primarily through glucuronide conjugation and beta-oxidation. The average elimination half-life of valproate is approximately 11 hours.[13] However, the elimination half-life of valproate can increase to 30 or more hours in the setting of acute overdose despite elimination via first-order kinetics.[14] In the setting of valproate toxicity, a greater degree of omega-oxidation occurs in the liver, which increases the risk of hepatotoxicity, cerebral edema, and hyperammonemia.[11] Cytochrome P (CYP)2C9 and CYP2A6 enzymes also play a role in valproate metabolism. Results from a recently published meta-analysis showed that patients with CYP2C9*3 and CYP2A6*4 genotype variants had higher serum valproate concentrations than patients without.[15]

Very little valproate is excreted in the urine as an unchanged drug. Aspirin increases free serum valproate levels by competing for plasma protein binding sites. Hypoalbuminemia, a condition common in patients who are older and in those with liver disease, also increases free serum valproate levels. Because total valproate serum levels may remain constant despite alterations in protein binding, measuring free or unbound serum levels is best practice in the setting of valproate toxicity.[16]

History and Physical

When assessing a patient with suspected valproate toxicity, clinicians should ascertain the specific time of valproate ingestion, valproate formulation, the amount of valproate ingested, other possible coingestants (eg, acetaminophen or alcohol), and a list of all of the patient's prior psychiatric or medical problems. Patients with acute ingestion of 200 mg/kg of valproate or serum valproate concentrations of 180 mg/L or greater often experience central nervous system dysfunction. Manifestations of central nervous system dysfunction include tremors, agitation, miosis, and other focal neurological deficits. Patients who experience valproate-related hyperammonemic encephalopathy may experience confusion, seizures, and lethargy, which can progress to stupor, coma, and death.[17][18] Additionally, patients with valproate toxicity may experience respiratory depression, hypotension, and tachycardia. Gastrointestinal symptoms consistent with valproate toxicity include vomiting, diarrhea, and abdominal pain.[11] 

Interestingly, the dermatohistopathology of valproate toxicity has been consistent with cases of hypersensitivity vasculitis and psoriasiform eruption. Patients on chronic valproate therapy may also exhibit symptoms consistent with alopecia due to telogen effluvium, including diffuse hair loss, thinning, and graying.[19] Valproate is also a potential teratogen. Fetal exposure to valproate during pregnancy can result in a wide range of congenital malformations, including spina bifida, anencephaly, craniofacial abnormalities, and genitourinary defects.[20]

Evaluation

Therapeutic serum concentrations of valproate usually range from 50 to 100 mg/L. Valproate levels should be obtained every 2 to 4 hours for patients with suspected valproate toxicity and until the serum valproate level starts declining. A steady decline in the level suggests a peak serum level has been reached.[21] Unbound valproate levels are an assessment tool in patients who are hypoalbuminemic, or when signs of valproate toxicity are present despite low or normal total valproate levels.[16]

Other important laboratory tests to order for patients with suspected valproate toxicity include a complete blood count with differential. If the patient is experiencing valproate toxicity, thrombocytopenia, and decreased granulocyte counts may be present. Additionally, a comprehensive metabolic panel is helpful to assess the patient for hypoglycemia, hepatotoxicity, electrolyte abnormalities, and acid-base disorders. Blood ammonia levels should be studied for patients experiencing encephalopathy. Toxicologic screening for coingestants, including other anticonvulsants, aspirin, and acetaminophen should also considered. A pregnancy test should be ordered for women of childbearing age.[21]

Other tests to consider include a 12-lead echocardiogram that shows an atrioventricular conduction block.[22] Sometimes, severe valproate toxicity is associated with atrial tachycardia.[23] A computed tomography scan of the head is necessary when patients present with signs of focal neurological deficits, profound central nervous system depression, or suspicion of cerebral edema.[19]

Treatment / Management

Initial therapy for patients with valproate toxicity should focus on medical stabilization and resuscitation. Specifically, initial interventions should focus on maintaining the airway, breathing, and circulation. Patients with severe respiratory depression may require endotracheal intubation and mechanical ventilation. Intravenous access may be needed to provide intravenous fluid and vasopressors for patients presenting with hypotension. Benzodiazepines should be administered if there is a seizure due to valproate toxicity.[24] (B3)

Other interventions to consider early for patients with valproate toxicity are gastrointestinal decontamination and lavage. If the patient presents within 2 hours of a valproate overdose, activated charcoal may be used for gastrointestinal decontamination. Valproate is available in enteric-coated and extended-release formulations, which have slow absorption. Administration of activated charcoal may be considered beyond 2 hours from ingestion for patients who have taken enteric-coated and extended-release valproate formulations.[25] The dose of activated charcoal is 1 g/kg of body weight. If the patient cannot swallow reliably, the administration of activated charcoal should be withheld. Gastric lavage may also be considered to eliminate valproate from the digestive tract. Food and Drug Administration guidelines indicate that gastric lavage treatment may be effective up to 10 or 12 hours after drug intake.[26] (B2)

After initial stabilization, it is prudent to consider the use of L-carnitine for patients presenting with an acute overdose of valproate and altered mental status. L-carnitine should be administered intravenously with a loading dose of 100 mg/kg, followed by 50 mg/kg intravenously every 8 hours. Serum ammonia levels should be simultaneously measured, and when serum ammonia levels start decreasing, L-carnitine therapy can be discontinued.[27] In the pediatric population, resulting evidence from a few case reports shows that carnitine may alter the generation of potentially toxic metabolites, but it may not translate into improved clinical prognosis.[28] Interestingly, the mu-opioid receptor antagonist naloxone may reverse the central nervous system depression in some cases of valproate poisoning.[29][30] Naloxone may also be useful for chronic valproate intoxication.[31](A1)

Hemodialysis is indicated for serum valproate concentrations greater than 1300 mg/L and in patients experiencing shock or cerebral edema. Hemodialysis can greatly reduce the elimination half-life of valproate. In one case study, hemodialysis decreased the half-life of valproate from 13 hours to 1.7 hours. Additionally, hemodialysis contributed to significant clinical improvement for the patient within 4 hours of treatment. Intermittent hemodialysis is the preferred technique for patients experiencing valproate toxicity, although continuous renal replacement therapy is an acceptable alternative if the patient cannot tolerate intermittent hemodialysis. Hemodialysis treatment can be discontinued if the serum valproate concentration drops below 100 mg/L and the patient shows signs of clinical improvement, including normotension, improved mental status, pH normalization, and resolution of electrolyte abnormalities.[32](A1)

Differential Diagnosis

Symptoms of valproate toxicity overlap with many conditions. Thus, a detailed history, physical examination, laboratory evaluation, and cerebral imaging are required to diagnose valproate toxicity.[33] The most common symptoms of valproate toxicity are altered mental status and central nervous system depression, which can be due to a wide range of conditions. Suspicion of meningitis should arise when a patient presents with fever and neck stiffness accompanied by altered mental status. 

Herpes simplex virus-1 encephalitis typically shows temporal lobe involvement in magnetic resonance images. Additionally, cranial neoplasm, intracranial hemorrhage, hydrocephalus, and traumatic brain injury should be ruled out as the cause of these symptoms. Valproate-induced tremors occur in about 10% of patients and require differentiation from essential tremors or tremors associated with Parkinson disease. 

A comprehensive metabolic panel should be ordered to search for metabolic derangements, including hypoglycemia and hypernatremia. As serum ammonia is frequently elevated with valproate poisoning, disorders of urea cycle disorders and hepatic encephalopathy should merit consideration. Finally, other causes of anion gap metabolic acidosis should be investigated. Common causes of anion gap metabolic acidosis include uremia, methanol poisoning, diabetic ketoacidosis, and lactic acidosis.

Prognosis

The prognosis for patients with valproate toxicity will depend on the total amount of valproate ingested, the opportunity to implement decontamination and elimination strategies, and the supportive care given. Severe ingestions may resolve without any sequelae after aggressive decontamination, elimination, and adequate supportive caIn one observational, retrospective study involving 316 patients, the prognosis of patients with acute valproate toxicity was good with supportive care alone. According to the multivariate analysis within the study, a coma during the initial presentation was associated with a poor prognosis. Other poor prognostic factors include advanced age, metabolic derangements, and ingesting large amounts of valproate.[34]

Complications

Acute valproate toxicity can result in dose-related and reversible hepatotoxicity. Usually, ceasing the drug therapy results in the normalization of liver function abnormalities, but fulminant hepatic failure and death have been reported with valproate toxicity.[35][36] Concerningly, liver transplants in children with valproate-induced acute hepatic failure have reduced survival rates compared to liver transplants from other causes of drug-induced liver injury.[37] Cerebral edema may lead to herniation, prolonged central nervous system depression, and coma.[11][14] Valproate-related hyperammonemic encephalopathy can lead to confusion, lethargy, and increased seizure frequency. If severe valproate toxicity is untreated, death may result.[38][39]