Apparent valproic acid neurotoxicity in a hypoalbuminemic patient

To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations.

A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 micrograms/mL, which was only slightly above the recommended therapeutic range (50-100 micrograms/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 micrograms/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction.

VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed.

It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.