Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure

Abstract

Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 µmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate). Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism

“…Neurotoxicity leading to coma and death is the most urgent issue in hyperammonemia from human urea cycle defects and other causes of severe hyperammonemia (27,32).…”

A Case of Suspected Urea Cycle Dysfunction in a Patient with Unexplained Hyperammonemia

“…Deficiency in any five of the enzymes in the urea cycle results in the accumulation of ammonia which could be potentially fatal if untreated. 7 Although usually seen in neonates, later cases of childhood and adulthood have been described. [1][2][3] The presentation can be atypical, with chronic vomiting, developmental delay, seizure disorder, sleep disorders, or psychiatric illnesses following increased protein intake or during periods of stress such as acute or chronic illness.…”

“…1 The amount of organic acids (orotic acids) in the urine may be difficult to detect in these patients because of the varying degree of enzymatic activity (lyonization). 7,8 The OTC gene has been found to exhibit enormous variation. More than 340 mutations have been identified in families in which there was clinical OTC deficiency.…”

Valproic acid induced hyperammonemic encephalopathy: A case report (Turkish)

“…Bu yayýnda psikiyatri alanýndan bildirilmiþ yaklaþýk 36 olgu olduðu belirtilmiþtir (6). Olgu sunumlarýnda, psikotik özellikli bipolar bozukluk tanýsý ile VPA kullanýlan bir hastada 3 kez hiperamonyemiye baðlanan hipoaktif deliryum (7); 11 yýldýr VPA tedavisi alan bir hastada akut hiperamonyemi ve deliryum (8) ve serum VPA düzeyi normal sýnýrlar-dayken hiperamonyemik ensefalopati geliþtiði (9) bildirilmiþtir. Hiperamonyemi durumunda sýklýkla bilinçte bozulma, letarji, koma görülmekte ve bu durum ölümle sonuçlanabilmektedir.…”