Chapter 6 142 becomes all the more difficult to recognize VPA as the cause of these symptoms when total blood VPA serum levels are within the reference range. Particularly in the elderly there is a risk of underestimationof the free fraction (Sajatovic, Madhusoodanan andCoconcea, 2005; Ng et al., 2009). There is evidence that the VPA affinity for serum proteins decreases with age and age is positively correlated with the free fraction (Kodama et al., 2002). The need for monitoring of the free concentration of VPA is suggested by multiple other case reports (De Maat, Van Leeuwen and Edelbroek, 2011; Jansen et al., 2012). Other cases have been published on VPA-induced encephalopathy due to hyperammonemia (Dealberto, 2007). In our case, ammonia (NH4) was not measured, it is therefore unclear if ammonia could have contributed to the symptoms. Development of hyperammonaemic encephalopathy is unrelated to VPA dose, serum level or severity of hyperammonaemia (Ng et al., 2009). 6.4 Conclusion As pointed out, due to the pharmacokinetics of VPA, patients with therapeutic total blood levels can have a high free concentration of VPA (Wallenburg et al., 2017) which can therefore be an undetected cause of side effects or even toxicity. This is more likely in hypoalbuminemic patients. We recommend measuring albumin during VPA use if free concentration VPA monitoring is not standard; particularly in patients at risk of hypoalbuminemia (Wallenburg et al., 2017), including those with nephrotic syndrome (Wallenburg et al., 2017), liver disease (Dasgupta, 2007; Wallenburg et al., 2017) or older adults (Sajatovic, Madhusoodanan and Coconcea, 2005; Ng et al., 2009; Wallenburg et al., 2017). This case report suggests that it is necessary to monitor the free concentration of VPA in hypoalbuminemic patients to prevent misinterpretation of side effects or toxicity.
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