Valproate-induced hyperammonemic encephalopathy associated with urinary tract infection and urinary retention in the psychiatric setting

To the Editor

Sodium valproate (VPA) is a common medication for epilepsy and psychiatric disorders and can induce hyperammonemia. In rare cases, valproate-induced hyperammonemic encephalopathy (VHE) may occur, presenting as lethargy, impaired consciousness, confusion, ataxia or coma (Chopra et al., 2012).

We present a 57-year-old male with a 30-year history of bipolar disorder on VPA 1 g mane 2 g nocte for 3-years, in combination with quetiapine and lithium. His co-morbidities included type-2 diabetes mellitus, chronic renal failure, hypertension and obesity.

He presented to a general medical unit in March 2015 with ataxia, confusion and falls and was treated for acute renal impairment, urinary retention and a urinary tract infection (UTI). He initially improved before again becoming confused, ataxic and irritable 18 days after presentation. He was transferred to an acute psychiatry unit to investigate a potential bipolar disorder exacerbation. A repeat delirium screen demonstrated creatinine elevated from baseline but no other abnormality. At day 19, ammonia was 126 umol/L (16–53 umol/L) with VPA level 1026 umol/L (300–700 umol/L) but normal range liver enzymes. VPA was ceased, with rapid clinical improvement and ammonia levels of 64 umol/L day 20 and 27 umol/L day 21. He returned to baseline mental state five days after ceasing VPA. VPA was re-trialled at a lower dose (500 mg bd), however, he again became confused and ataxic with ammonia 65 umol/L.

Risk factors for VHE include polypharmacy, medical co-morbidities, the peri-operative period, dietary factors, carnitine deficiency and urea cycle disorders (Chopra et al., 2012), and pathophysiology is multifactorial (Lewis et al., 2012).

Chronic renal impairment is associated with carnitine deficiency through impaired endogenous carnitine biosynthesis. Carnitine is required for hepatic metabolism of VPA and reduced levels impair VPA metabolism in the liver, which produces toxic metabolites including ammonia (Lewis et al., 2012).

UTI with urinary retention has been linked with hyperammonemic encephalopathy in patients not on VPA (Sato et al., 2008). Urease positive bacteria can cleave urea to ammonia in the bladder, which then diffuses over the increased surface area of the distended bladder wall, causing high ammonia.

Through the mechanisms described above, this patient’s UTI and urinary retention could have precipitated VHE through increased production and absorption of ammonia across the bladder wall, with impaired renal function compounding the ammonia rise through carnitine deficiency. VHE should be considered in patients presenting with altered conscious state while on VPA even with long-term treatment and normal range liver enzymes.