Valproate-induced hyperammonemic encephalopathy

Last revised by Rohit Sharma on 22 Feb 2024

Valproate-induced hyperammonemic encephalopathy (VHE), also known as valproic acid-induced hyperammonemic encephalopathy, is a rare type of non-cirrhotic hyperammonemic encephalopathy caused by use of sodium valproate, a drug commonly used as an antiseizure medication and mood stabilizer.

Valproic acid-induced hyperammonemia is common, with reported rates of 35-45% 1, however a resultant encephalopathy is rare, although the exact incidence of VHE is unknown. 

VHE is more common in certain individuals 2,3:

  • patients with urea cycle enzyme deficiencies (e.g. ornithine transcarbamylase deficiency)

  • patients with liver disease

  • use of other drugs that interfere with the urea cycle (e.g. topiramate)

  • strict vegetarians

VHE has a varied and non-specific acute or subacute presentation, that can manifest within weeks to years after initiation of treatment 2,3. Possible clinical features including focal neurological deficits, vomiting, and decreased conscious state (including coma) 2,3. In patients taking sodium valproate as an antiseizure medication, VHE can result in an increased frequency of seizures 2.

Biochemically, patients usually have a normal liver function profile (unless concomitant liver disease), and interestingly, sodium valproate levels are often in the therapeutic range even in severe hyperammonemia 2,3. Furthermore, the degree of hyperammonemia does not correlate with the severity of encephalopathy 2,3.

There are several proposed mechanisms regarding the development of hyperammonemia during both therapeutic use and overdose with valproic acid all of which converge on dysfunction of the urea cycle as the proximal cause 1-3.

The metabolism of valproic acid is primarily hepatic with less than 3% of the unchanged drug renally excreted. During therapeutic use the primary means of metabolism occurs through (cytosolic) conjugation with glucuronide and (mitochondrial) beta oxidation; the latter is accomplished by cytosolic conjugation to carnitine, transport into the mitochondrion in exchange for free carnitine, conjugation to coenzyme A with subsequent oxidation in an analogous manner to long chain fatty acid metabolism 9.

Conjugation with carnitine may result in its deficiency by diffusion out of the hepatocyte and renal loss, as well as inhibiting the carnitine uptake transporter. Sequestration of coenzyme A decreases fatty acid beta-oxidation and intra-mitochondrial acetyl-CoA, the latter which is required for not only the function of the citric acid cycle (decreased ATP production) but also the formation of N-acetylglutamate, which is a required cofactor in the rate-limiting step of urea formation from ammonium 10. Metabolites of cytosolic omega oxidation may also contribute.

The consequent hyperammonemia likely significantly contributes to the associated neurotoxicity via enhancing excitatory neurotransmission as well as astrocytic accumulation and cerebral edema 2,3. The mitochondrial toxicity and impairment of lipid metabolism may also result in microvesicular steatosis and hepatotoxicity in a similar manner to Reye syndrome.

Radiographic features are rarely reported in the literature, and mainly concern MRI brain findings 4-6.

Across the very few studies reporting MRI features of VHE, the following characteristics have been described:

  • T2/FLAIR: bilateral symmetric regions of high signal within the cerebral cortex (especially frontal and insular cortices) 4,5, cerebellar white matter 6, and globus pallidi 6

  • DWI: similar distribution of high diffusion signal to T2/FLAIR 5

  • MR spectroscopy: elevated glutamine/glutamate peak with decreased myoinositol and choline peaks on proton MR spectroscopy 6

Following treatment (see below), there is resolution of aforementioned signal changes 4.

The mainstay of treatment is cessation of sodium valproate therapy 2,3. Hyperammonemia can additionally be managed with medications such as lactulose or L-carnitine 2,3. Prognosis is generally excellent, with complete recovery observed within days of sodium valproate cessation 2,3.

Patients affected by VHE should also be opportunistically screened for urea cycle deficiencies, such as being asymptomatic heterozygotes for ornithine transcarbamylase deficiency 2.

The differential diagnosis includes other causes of hyperammonemic encephalopathy, such as hepatic encephalopathyadult-onset citrullinaemia, and late-onset ornithine transcarbamylase deficiency 7,8.

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