Valproate Use Is Associated With Posterior Cortical Thinning and Ventricular Enlargement in Epilepsy Patients

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.

Keywords: brain morphometry; brain structure; cortical thickness; epilepsy; valproate.

Figure 1

Study flow-chart. See text for inclusion/exclusion criteria. VPA+, patients using valproate at the time of MRI study. VPA-, patients using antiepileptic drugs other than valproate.

Figure 2

Cortical thickness difference between valproate users and non-valproate users. Surface brain template showing regions of cortical thinning in valproate users compared to non-valproate users. Brain images are generated using EnigmaViewer (https://www.nitrc.org/projects/enigmaviewer_20/); strength (color) of heat map is determined by the size of the regional effect size estimate. Effect size estimates (partial eta squared, y-axis) for cortical thickness differences across all brain regions is showed on the bar plots. Brain regions with significant differences between groups (p < 0.05 FDR; ANCOVA analysis adjusted for age, sex, disease duration, and intracranial volume) are reported on the x-axis. Lh, left hemisphere; Rh, right hemisphere.

Figure 3

Cortical thickness difference between valproate users and drug-naïve patients. Surface brain template showing regions of cortical thinning in valproate users compared to drug-naïve patients. Brain images are generated using EnigmaViewer (https://www.nitrc.org/projects/enigmaviewer_20/); strength (color) of heat map is determined by the size of the regional effect size estimate. Effect size estimates (partial eta squared, y-axis) for cortical thickness differences across all brain regions is showed on the bar plots. Brain region with significant differences between groups (p < 0.05 FDR; ANCOVA analysis adjusted for age, sex, disease duration, and intracranial volume) are reported on the x-axis. Lh, left hemisphere; Rh, right hemisphere.

Figure 4

Volume of the lateral ventricles (means, mm³) in the different groups. VPA+ (^*) and VPA mono (^**) groups showed enlarged ventricular volumes (both right and left ventricle) with respect to every other group. No significant differences were present for healthy controls, VPA-, and drug-naïve groups (see text and Table 3). VPA+: epilepsy patients using valproate (in mono or polytherapy); VPA-, patients not using valproate; VPA mono, patients using valproate in monotherapy. Bars represent the standard error of the mean.