The BrainDrugs-epilepsy study: A prospective open-label cohort precision medicine study in epilepsy

Abstract

Introduction: The BrainDrugs-Epilepsy Study is part of the established Lundbeck Foundation funded BrainDrugs research alliance (braindrugs.nru.dk). The study aims to identify biomarkers of treatment outcome as well as cognitive and psychiatric comorbidity in patients with a first epileptic seizure and epilepsy. Our goal is to provide a patient-level prediction of treatment response.

Methods: In a prospective cohort study design, we will consecutively include a total of 200 patients who have experienced their first epileptic seizure and 150 newly diagnosed patients with epilepsy ( $\ge$ 16 years old). We will systematically collect data at baseline and one, three, and five years after inclusion. Neuropsychiatric and neuropsychological assessments will be combined with electroencephalography (EEG) and neuroimaging tools such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) brain scans using the synaptic vesicle glycoprotein 2A-binding radioligand [¹¹C]-UCB-J. After completing the baseline investigations, patients diagnosed with epilepsy start anti-seizure medication (ASM) treatment with either lamotrigine or levetiracetam. Patients will be monitored every three months. For daily monitoring, we will use a mobile app. Our clinical endpoints are 1) ASM treatment response, 2) development of a second seizure/epilepsy diagnosis, 3) psychiatric symptoms, 4) cognitive disturbances, and 5) quality of life.

Discussion: We hypothesize that seizures, cognitive impairment, and psychiatric symptoms share common neurobiological mechanisms that can be identified using MRI, PET, and EEG. We will assess how these biomarkers change over time and in response to treatment, providing novel insights into disease trajectories in the first years of epilepsy.

Clinical trial registration: NCT05450822. Retrospectively registered July 5, 2022 (https://clinicaltrials.gov/ct2/results?term=NCT05450822&Search=Search).

Keywords: Biomarkers; Epilepsy; Machine learning; Neuroimaging; Precision medicine; Treatment response.

Fig. 1

Workflow of The BrainDrugs-Epilepsy Study Cohort I-III and healthy controls. EEG: Electroencephalography. MRI: Magnetic resonance imaging. PET: Positron emission tomography.

Fig. 2

Illustration of latent variable model and result outputs for the [¹¹C]-UCB-J binding in epilepsy patients with and without depression ^γ is the effect of group status on the global (log-transformed) [¹¹C]-UCB-J binding, β coefficient represents the loading of the region-specific binding. The bottom boxes indicate, for each brain region, the percentage difference in [¹¹C]-UCB-J binding between epilepsy patients with and without depression (additionally, p-values and confidence intervals adjusted for multiple comparisons will be added). Age, sex, scanner type and injected mass/kg, etc., will be included as covariates in the model. PFC: Prefrontal cortex. OFC: Orbitofrontal cortex. ACC: Anterior cingulate cortex.