Cognitive impairment during therapeutic total VPA concentration 6 141 and she regained conative, cognitive, affective, and physical functioning within days with independency in Activities of Daily Living (ADL). On day 154 she was transferred to the psychmed-unit for further recovery in Instrumental Activities of Daily Living (IADL). Liver function test results were within reference ranges, except for a gamma-glutamyltransferase (GGT) of 58 U/l and alkaline phosphatase (ALP) of 127 U/l. Her cognitive and conative functioning recovered to pre-VPA levels (MMSE 27/30, MoCA 27/30, GDS 1). Discharge followed 197 days after introducing VPA. Later that year lithium was reintroduced without problems. 6.3 Discussion The cognitive impairment that started just days before admission to the psych-med unit was thought to be partially related to age, manic state, neurodegenerative, lithium intoxications and due to a recent delirium. Change of health care professional contributed to the misinterpretation of cognitive side-effects, as her baseline MoCA score was not transferred from the outpatient clinic. Lithium was thought to be associated to the cognitive decline, due to cognitive complaints during the first and second reintroduction, although there were concurrent deliria and a dosage increase of VPA to 4000mg. Reintroduction of lithium (up to 1.2mmol/l) following dechallenge of VPA did not result in cognitive impairment. The cognitive impairment couldbe categorizedas adefiniteadverseevent of VPA (Naranjo score9) (Naranjo et al., 1981). VPA was at first neglected as a causal factor, since the tVPAc was below or within the therapeutic range. However, the eventually detected free concentrations of VPA were far above the reference range and are likely to have caused the severe reversible cognitive impairment. The patient’s hypoalbuminemia explains the remarkably high free fraction of VPA and was most likely caused by the PLA2R membranous nephropathy. There was a time-correlation with the tVPAc, free concentration and the severity of cognitive impairment (Figure 1). The cognitive impairment started after a dosage increase of VPA to 4000mg. Her albumin levels dropped starting day 96 from a low but stable 23- 26 g/l to 14 g/l on day 124 which could explain why the clinical condition deteriorated dramatically. We presume the free concentration could have net increased more due to decreased albumin despite the lowering of the dosage. Dechallenge of VPA gradually resulted in a continuous revitalization. Previous cases have reported VPA related dementia and cognitive impairment, even after long-termuse (Evans, Shinar and Yaari, 2011). Cognitive and conative side effects are known to arise in VPA treatment, although very rarely as severely as seen in our patient. A difficulty is that these features, along with other known side effects such as decreased appetite, apathy, aggression, and hyperactivity, can be symptoms of the diseases VPA is given for, particularly bipolar depression and mania. These adverse effects may be misinterpreted, especially when they are less pronounced, progress over time and with advancing age. It
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