Sodium Valproate Modulates Cortical Morphology in Juvenile Myoclonic Epilepsy

Importance: Idiopathic generalized epilepsy syndromes in are associated with cortical thinning of the premotor areas. Whether this represents an underlying disease signature, a consequence of seizure activity or is related to anti-seizure medication is unknown. Objective: To investigate valproate-related effects on cortical morphology in people with juvenile myoclonic epilepsy (JME), one of the most common IGE syndromes. Design: Retrospective neuroimaging case-control study. Setting: Recruitment took place in epilepsy clinics in two European epilepsy referral centers. Participants: We matched individuals with JME on valproate (n=36) to a group of healthy controls (n=36), as well as individuals with JME not on valproate (n=36) and a group of people with temporal lobe epilepsy (n=19) on valproate using propensity scores for age, sex, occurrence of bilateral tonic-clonic seizures and drug refractoriness. Main outcomes and Measures: All participants underwent structural T1-weighted brain imaging and MRI-derived vertex-wise measurements of cortical thickness were calculated. Results were reported in effect-sizes using cohen's d. Results: Compared to healthy controls, individuals with JME on valproate demonstrated cortical thinning bilaterally in the precentral gyri (left: d = -1.0, p <.001; right: d = -1.0, p <.001). This effect was localized to the left precentral gyrus when comparing JME on VPA with individuals with JME not on valproate (d = -0.89; p <.01) or with individuals with temporal lobe epilepsy on valproate (d = - 0.18, p <.001). No significant differences in cortical thickness were detected between individuals with JME not on valproate and healthy controls. Cortical thinning in precentral gyrus, postcentral gyrus and superior frontal was more marked with increasing valproate dose (left: t = -6,65, p <.0001; right: t = -5,20, p <.0001). Conclusions and Relevance: In this cross-sectional study of 91 patients with epilepsy, valproate treatment was associated with JME-specific and dose-dependent cortical thinning of the precentral gyri. Our findings suggest a valproate-induced reorganization of disease-specific areas in JME that may not only help explain the high efficacy of this medication in IGEs but also potentially account for previously described changes of cortical thickness in this disease group. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by an Austrian Science Fund (Fonds zur Foerderung der Wissenschaftlichen Forschung) grant awarded to ET (project number KLI 969), a Wellcome Trust grant awarded to MJK (079474) and a Henry Smith Charity grant awarded to MJK and BW (20133416). BCP was supported by a scholarship from the Austrian Society of Epileptology. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of University College London Hospitals and the State of Salzburg gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors.