Abstract
Valproate is a drug widely used to treat epilepsy, bipolar disorder, and occasionally to prevent migraine headache. Despite its clinical efficacy, prenatal exposure to valproate is associated with neurodevelopmental impairments and its use in children and adults was associated with rare cases of reversible brain atrophy and ventricular enlargement. To determine whether valproate use is related with structural brain changes we examined through a cross-sectional study cortical and subcortical structures in a group of 152 people with epilepsy and a normal clinical brain MRI. Patients were grouped into those currently using valproate (n = 54), those taking drugs other than valproate (n = 47), and drug-naïve patients (n = 51) at the time of MRI, irrespectively of their epilepsy syndrome. Cortical thickness and subcortical volumes were analyzed using Freesurfer, version 5.0. Subjects exposed to valproate (either in mono- or polytherapy) showed reduced cortical thickness in the occipital lobe, more precisely in the cuneus bilaterally, in the left lingual gyrus, and in left and right pericalcarine gyri when compared to patients who used other antiepileptic drugs, to drug-naïve epilepsy patients, and to healthy controls. Considering the subgroup of patients using valproate monotherapy (n = 25), both comparisons with healthy controls and drug-naïve groups confirmed occipital lobe cortical thickness reduction. Moreover, patients using valproate showed increased left and right lateral ventricle volume compared to all other groups. Notably, subjects who were non-valproate users at the time of MRI, but who had valproate exposure in the past (n = 27) did not show these cortical or subcortical brain changes. Cortical changes in the posterior cortex, particularly in the visual cortex, and ventricular enlargement, are present in people with epilepsy using valproate, independently from clinical and demographical variables. These findings are relevant both for the efficacy and adverse events profile of valproate use in people with epilepsy.
Highlights
Valproate (VPA) is a drug widely used to treat epilepsy, bipolar disorder, and occasionally to prevent migraine headache
Its use in females must be carefully evaluated since recent evidence shows that prenatal exposure to valproate is associated with neurodevelopmental impairments, impaired language and intellectual abilities and with structural brain cortical changes, suggesting an effect of this drug on the prenatal brain [10, 11]
Pardoe and colleagues evaluated brain structural measures in seven patients with epilepsy taking valproate compared to normal controls and to people with epilepsy not taking valproate: they found that total brain volume, white matter volume, and parietal cortical thickness were reduced in the valproate group relative to controls and non-valproate users; in addition, when comparing pastvalproate users with patients who had never taken valproate, no differences in brain structures emerged, suggesting that valproate-related alterations were transient and reversible [17]
Summary
Valproate (VPA) is a drug widely used to treat epilepsy, bipolar disorder, and occasionally to prevent migraine headache. Its use in females must be carefully evaluated since recent evidence shows that prenatal exposure to valproate is associated with neurodevelopmental impairments, impaired language and intellectual abilities and with structural brain cortical changes, suggesting an effect of this drug on the prenatal brain [10, 11]. Valproate use was associated with rare cases of reversible brain atrophy and ventricular enlargement with accompanying cognitive impairment or parkinsonism [12,13,14]. In Alzheimer’s Disease, valproate use was related to accelerated brain volume loss, in particular with ventricular enlargement and hippocampal atrophy, and greater cognitive impairment [15, 16]. This study had not investigated the possible effects of antiepileptic drugs on brain structures
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