Valproate Toxicity Clinical Presentation

Updated: Oct 25, 2021
  • Author: Asim A Abbasi, MD, FAAP; Chief Editor: Michael A Miller, MD  more...
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Few historical features are specifically suggestive of valproate (valproic acid [VPA]) toxicity. As in most poisonings, a clinical history of the ingestion, including the amount and exact time of ingestion, is helpful. Adequate documentation of previous medical and psychiatric problems is essential.

Prescription and nonprescription medications (including over-the-counter drugs and drugs of abuse) may contribute or mask symptoms of overdose. Accordingly, all medications taken must be documented. The possibility of other coingestions not reported by the patient, family, or prehospital providers (including herbal and natural remedies) must also be considered.

The exact time of the overdose should be recorded if possible. The VPA formulation (eg, capsules, sprinkles, syrup, or extended-release tablets) should be noted, as should the exact amount taken. In particular, divalproex and extended-release formulations may cause significant delays in peak concentration during overdose.

The remaining or unused amount in the prescription bottle should be counted or measured and subtracted from the original amount dispensed from the pharmacy. A discrepancy between the amount actually missing and the amount that should be missing if the prescribed regimen was correctly followed provides a rough estimate of the amount the patient may have taken.

Previous suicidal attempts should be inquired into; these are important in that they can lead the clinician to consider referring the patient to a psychiatrist. If a patient continues to have suicidal ideation, holding him or her for psychiatric evaluation on legal grounds may be warranted.

All patients with VPA overdose should also be screened for domestic violence. Because domestic violence is widely underreported, it is important to be aware of and alert to other potential indications of such abuse, including assault, depression, and suicide attempts.


Physical Examination

Physical examination may provide clues to the nature of the poisoning. Physical findings may help in determining the severity of the overdose, but they are not specific for VPA overdose. Gastrointestinal (GI) upset with nausea and vomiting is the most common presentation of patients with VPA overdose, closely followed by central nervous system (CNS) symptoms of decreased consciousness level and confusion.

Altered vital signs

Vital signs are highly variable in patients with VPA poisoning. Both fever and hypothermia have been reported.

Hypotension has been reported with severe overdoses. Many case reports of severe VPA overdose discuss hypotension refractory to aggressive use of intravenous (IV) fluids and pressor agents. In a large multicenter review of 134 patients (80 of whom had VPA levels in the toxic range), 3% of patients had hypotension in association with acute VPA ingestion, and 25% of patients with levels above 850 mg/L had hypotension. [13] VPA levels above 1000 mg/L may be associated with refractory hypotension.

The risk of hypotension notwithstanding, hemodialysis is often recommended for these patients to achieve a rapid increase in elimination, on the grounds that these high VPA levels are associated with severe morbidity and mortality. Hemodialysis is often effective and may produce dramatic improvements for these patients.

Cardiac arrest has been reported in severe VPA overdoses. The clinical condition of patients with VPA overdose can worsen dramatically as the drug is being absorbed. In cases involving a massive overdose, apnea and cardiac arrest can develop.

Respiratory depression necessitating intubation occurs with increasing frequency as VPA levels rise.

CNS manifestations

CNS findings in cases of VPA overdose may include the following:

  • Coma

  • Confusion

  • Somnolence

  • Worsened seizure control

  • Dizziness

  • Hallucinations

  • Irritability

  • Headache

  • Ataxia

  • Cerebral edema - This well-documented manifestation usually occurs 48-72 hours after ingestion, even as serum levels are decreasing

In a large multicenter review of 134 patients (80 with VPA levels in the toxic range), 71% of patients presented with lethargy, and 15% were comatose. [13] All patients with serum levels greater than 850 mg/L were comatose, and 63% of these patients needed intubation.

It has been suggested that elevated serum ammonia levels can produce encephalopathy via the inhibition of glutamate uptake by astrocytes, which may lead to potential neuronal injury and perhaps cerebral edema. It has also been suggested that hyperammonemia may lead to a disruption of the osmotic gradient, which is thought to precipitate the edema. [14]

This valproate-induced hyperammonemic encephalopathy [15] may be an adverse effect of the drug and is characterized by lethargy, vomiting, altered cognitive function, focal neurologic deficits, and decreased level of consciousness. Its onset or severity may not be related to the drug dosage administered or to the duration of previous treatment.

In contrast, Caruana Galizia and colleagues report a case of akinetic-rigid syndrome, with ataxia and marked cognitive impairment, that developed in a patient on long-term valproate therapy. The patient's serum ammonia and valproate levels were normal, but after withdrawal of valproate, her motor symptoms resolved within 2 weeks and her cognitive impairment markedly improved. [16]

Other findings

Additional physical findings that may be noted in patients with valproate toxicity include the following:

  • Dermatologic - Alopecia has been reported in severe and chronic overdose

  • GI - Anorexia, nausea, and vomiting are the most common symptoms in acute toxicity

  • Genitourinary (GU) - Renal failure is rare; case reports describe renal failure in patients with serum VPA levels higher than 1000 mg/L; anuria and enuresis may be noted

  • Musculoskeletal - Patients may present with tremors and chorea

  • Ocular - Miosis and nystagmus may be observed