Precision Medicine in the Treatment of Epilepsy

Epilepsy Clinical Trial

— BDE  

Official title:

The BrainDrugs-Epilepsy Study: A Prospective Open-label Cohort Precision Medicine Study in Epilepsy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05450822
• Other study ID #: H-21031962
• Status: Recruiting
• Start date: February 18, 2022
• Est. completion date: December 31, 2031

Study information

• Verified date: April 2024
• Source: Rigshospitalet, Denmark
• Contact: Maja Marstrand-Jørgensen, MD
• Phone: +45 35 45 36 43
• Email: maja.marstrand-jorgensen[@]nru.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Primary objectives:

The purpose of this study is to identify single and composite biomarkers (from neuroimaging, electrophysiological, and non-imaging biological measures), clinical measures (from cognitive, psychometric, and behavioral test scores), and risk/protective factors (e.g., from medical history, socioeconomic status, coping, lifestyle) that can:

1. Predict antiseizure medication (ASM) treatment outcome, psychiatric, cognitive, or behavioral comorbidities, and quality of life in newly diagnosed epilepsy patients (Cohort II-III).

2. Predict a second epileptic seizure/epilepsy diagnosis and behavioral, cognitive, psychiatric dysfunction and quality of life in patients after a first epileptic seizure (Cohort I).

Description:

Material and methods:

The BrainDrugs Epilepsy Study will be conducted as an open, longitudinal, prospective cohort study. The study consists of three patient cohorts:

Cohort I includes patients with a first epileptic seizure who will undergo basic clinical, cognitive, psychometric, and biological (blood) assessment, as well as electroencephalography (EEG) and Magnetic Resonance Imaging (MRI) neuroimaging.

Cohort II includes patients newly diagnosed with epilepsy who will undergo additional clinical, cognitive, psychometric, and biological (blood and stool) assessment as well as EEG and MRI neuroimaging.

Cohort III includes a subset of patients from Cohort II who they also undergo Positron Emission Tomography (PET) synaptic vesicle glycoprotein 2A (SV2A) neuroimaging.

Data from healthy controls will be collected, the investigative program for whom will be similar to that of Cohort III.

After completing the baseline investigation program, patients diagnosed with epilepsy will start ASM treatment with lamotrigine or levetiracetam, in accordance with standard treatment procedures. If the first ASM does not lead to seizure-freedom, the patients will be offered to switch to the other. Patients will be monitored every three months in the epilepsy outpatient clinic or by video or telephone consultations. For daily monitoring, a digital solution will be used, including a mobile app for patients and a web dashboard for health professionals

The mobile app contains a study module with content tailor-made for the BrainDrugs Epilepsy Study. Patients will be instructed to use the app once daily to register compliance and disease progression. Patients will complete monthly questionnaires (NDDI-E, GAD-7, LAEP, PGIC, SSQ, STAXI-2 and WHO-5) through the app tracking depressive symptoms, anxiety, adverse reactions, treatment response, seizure frequency and severity, aggression, and quality of life.

The investigators aim to include a total of 350 patients and 50 healthy subjects during the first three years of the study. All patients will be followed for five years. In addition, data from Danish health registries and electronic patient records will be used to characterize patients both retrospectively (e.g., information about birth complications) and prospectively (e.g., clinical status) during the study period.

In Cohort I, investigators will include a total of 200 patients (≥16 years old) who have been referred to clinical care after experiencing their first epileptic seizure, but do not fulfil the diagnostic criteria for epilepsy. In Cohort II, investigators will include a total of 150 newly diagnosed patients with epilepsy (≥16 years old). During the observational period, investigators expect at least 70 patients from Cohort I to be diagnosed with epilepsy upon experiencing their second epileptic seizure. These patients will subsequently be included in Cohort II. Lastly, Cohort III will be a subset of approximately 45 adult patients (≥18 years old) from Cohort II with focal onset seizures who will undergo investigation with PET.

After inclusion in the study, the patients will undergo an examination program at baseline and follow-up (1, 3 and 5 years after inclusion) that includes a study nurse interview with setup of the mobile app, neuropsychiatric interview and examination, neuropsychological tests and self-report questionnaires, high density EEG, MRI brain scan including (T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), arterial spin labeling (ASL) and functional magnetic resonance imaging (fMRI)) and blood and urine samples as well as gut microbiome samples (Cohort II-III). In addition, adult patients in Cohort III will undergo a [11C]-UCB-J PET brain scan followed by intravenous administration of levetiracetam (LEV) in a displacement paradigm.

For patients in Cohort III treated with LEV, if both symptoms and extended examinations are compatible with either 1) the development of an epilepsy-related comorbidity, 2) clinically significant adverse reactions or adverse events, 3) drug treatment failure, or 4) drug resistance, a repeated [11C]-UCB-J PET brain scan will be acquired prior to change in ASM treatment.

After inclusion in the study all healthy controls (HCs) will undergo an examination program similar to Cohort III. HCs will not be followed over time. The mobile app will only be used by patients.

Primary hypotheses:

1. Combined biomarkers from morphometric measurements (e.g., the volume of thalamus and hippocampus, cortical thickness of precentral gyri, parahippocampal cortex, entorhinal and fusiform gyri, precuneus, frontal gyri), within-network resting-state functional connectivity (rsfMRI), whole-brain structural connectomics (Diffusion Tensor Imaging, DTI) and functional connectivity in the theta band (EEG) at baseline can be used to predict the chance of a recurrent seizure (Cohort I).

2. Combined biomarkers from morphometric measurements (e.g., the volume of amygdala and hippocampus, cortical thickness of orbitofrontal cortex), resting-state functional connectivity in the anterior cingulate cortex, between prefrontal-limbic systems, angular gyrus, temporal lobe, precuneus, cerebellum, default mode network, and executive control network (rsfMRI), structural connectivity between temporal lobe, the limbic system and orbitofrontal cortex (DTI) and functional connectivity in the anterior cingulate cortex, frontal and occipital alpha asymmetry and theta current source density in the anterior cingulate cortex (EEG) at epilepsy diagnosis can be used to predict the risk of developing drug-failure and epilepsy-related comorbidities (Cohort II-III).

3. Cerebral [11C]-UCB-J binding at baseline both globally and in primary volumes of interest, i.e., hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala correlate negatively with epilepsy-related comorbidities e.g., depressive episodes and cognitive deficits (Cohort III and healthy).

4. Cerebral [11C]-UCB-J PET SV2A occupancy following a displacement paradigm with levetiracetam is associated with a decrease in cerebral blood flow in the epileptogenic lesions(s) (patients) and in primary volumes of interest, i.e., hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate, and amygdala cortex in healthy controls and in patients who become seizure free with levetiracetam treatment (Cohort III and healthy).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 550
• Est. completion date: December 31, 2031
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 16 Years to 55 Years

Eligibility

Inclusion Criteria for healthy subjects:

• No history of current or past psychiatric or other major medical conditions

Exclusion Criteria for healthy subjects:

• Current or previous neurological disease, severe somatic disease, or consumption of medical drugs likely to influence the test results

• Non-fluent in Danish or pronounced visual or auditory impairments

• Current or past learning disability

• Pregnancy or lactation (females)

• Participation in experiments with radioactivity (>10 mSv) within the last year or significant occupational exposure to radioactivity

• Contraindications for MRI (pacemaker, metal implants, etc.)

• Severe head injury

• Alcohol or drug abuse

• Drug use other than tobacco and alcohol within the last 30 days

• Hash > 50 x lifetime

• Drugs > 10 x lifetime (for each substance)

• Current psychoactive medication

• Any current or former primary psychiatric disorder (Axis I WHO ICD-10 diagnostic classification)

Inclusion Criteria for patients:

• Cohort I-II: Age between 16 and 55 years

• Cohort III: Age between 18 and 55 years

• Cohort I: Semiology of first seizure raises a strong suspicion of epilepsy but do not fulfill International League Against Epilepsy (ILAE) diagnostic criteria

• Cohort II-III: Diagnosed with epilepsy according to ILAE criteria

• Cohort III: Epileptogenic lesion on MRI concordant with seizure semiology and/or EEG

Exclusion criteria for patients:

• Cohort I-III: Life expectancy < 10 years

• Cohort I-III: Known genetic syndromes, psychomotor retardation or disease associated with gross morphological brain changes such as brain tumor, major stroke or major traumatic brain injury

• Cohort I-III: Body weight less than 40 kg

• Cohort I-III: Reduced kidney function (i.e., glomerular filtration rate (GFR) < 80 ml/min or 50 ml/min for patients 16-17 years old or =18 years old, respectively),

• Cohort I-III: Moderate reduced liver function

• Cohort I-III: Cardiac conduction disorders (e.g., Brugada syndrome, long QT-syndrome)

• Cohort I-III: Medication incompatible with study aims or causing interactions with the administered levetiracetam or lamotrigine therapy (e.g., SV2A binding agents, monoamine oxidase inhibitors, fluvoxamin, methotrexate, benzodiazepines, phenobarbital, carbamazepine, valproate, regular use of other ASMs)

• Contraindication for MRI (e.g., magnetic implants, pacemaker)

• Inability to complete PET (Cohort III) or MRI scans (Cohort I-III) (e.g., claustrophobia, issues with back pain)

• Cohort III: Exposure to radioactivity >10 mSv within the last year or significant occupational exposure to radioactivity

• Pregnancy or lactation

• Cohort I-III: Non-fluency in Danish or pronounced visual or auditory impairments or severe intellectual disability

• Cohort I-III: Current or previous alcohol or drug abuse

Related Conditions & MeSH terms

• Epilepsy

Intervention

Drug:
• Levetiracetam
Healthy subjects and patients in Cohort III will undergo a 120 min. [11C]-UCB-J PET-MR brain scan followed by intravenous administration of levetiracetam after approx. 60 min. in a displacement paradigm. Before, during and after the intervention arterial spin labeling and resting-state functional MRI will be acquired. To measure the radiolabelled tracer's arterial input function, including its radiolabelled metabolites, blood samples will be drawn during the PET scan from an arterial catheter. The selected regions for the primary analyses are the epileptogenic lesion(s) (patients) and the neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala. [11C]-UCB-J binding, volume of distribution and SV2A occupancy will be quantified by analyzing the PET images with well-validated kinetic models.
• Levetiracetam Tablets
Patients in Cohort II will be randomized to treatment with an ASM (levetiracetam) in accordance with standard treatment procedures. The patients will enter a 4 weeks titration period receiving increasing doses. During weeks 5-30, patients will enter an evaluation period where the dose can be increased (continued seizures) or decreased (adverse reactions). In cases of unacceptable seizure control and/or intolerable adverse reactions; shift to lamotrigine arm.
• Lamotrigine tablet
Patients in Cohort II will be randomized to treatment with an ASM (lamotrigine) in accordance with standard treatment procedures. The patients will enter a 6 weeks titration period receiving increasing doses. During weeks 5-30, patients will enter an evaluation period where the dose can be increased (continued seizures) or decreased (adverse reactions). In cases of unacceptable seizure control and/or intolerable adverse reactions; shift to levetiracetam arm.

Locations

Country	Name	City	State
Denmark	Neurobiology Research Unit, Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Gitte Moos Knudsen

Country where clinical trial is conducted

Denmark, 

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* Note: There are 194 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Continuous treatment outcome rating state aggression (Cohort II-III and healthy).	Treatment outcome as percentage change in the State-Trait Anger Expression Inventory 2 (STAXI-2).	At baseline between groups (HCs and patients) and as a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III.
Other	Continuous treatment outcome rating trait aggression (Cohort II-III and healthy).	Treatment outcome as percentage change in the Aggression Questionnaire (AQ).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Continuous treatment outcome as a measure of self-management of epilepsy (Cohort II-III).	Treatment outcome as percentage change in the Epilepsy Self-management Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Continuous treatment outcome as a measure of expectations to treatment outcome (Cohort II-III).	Treatment outcome as percentage change in the Epilepsy Outcome Expectancy Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Continuous outcome as epilepsy stigmatization (Cohort II-III).	Percentage change in the Epilepsy Stigmatization Scale.	As change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	A continuous rating of depression (Cohort I-III and healthy).	Percentage change in the Becks Depression Inventory (BDI).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of subjective, cognitive complains (Cohort I-III and healthy).	Percentage change in the self-report Cognitive Complaints in Bipolar Disorder Rating Assesment.(COBRA).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of perceived stress (Cohort I-III and healthy).	Percentage change in the Cohen's Perceived Stress Scale (PSS).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of personality traits (Cohort I-III and healthy).	Percentage change in NEO Personality Inventory 3 (NEO-FFI-3).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of the psychological impact of traumatic event (first seizure/epilepsy diagnosis) (Cohort I-III).	Percentage change in Impact of Event Scale-Revised (IES-R).	As change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of coping strategies (Cohort I-III and healthy).	Percentage change in Coping Self-Efficacy Scale (CSES).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Continuous outcome of sleep quality (Cohort II-III and healthy).	Percentage change in Pittsburgh Sleep Quality Index (PSQI).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Continuous outcome of negative life events (Cohort II-III and healthy).	Percentage change in Stressful Life Event scale (SLE).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Genotyping of epilepsy candidate genes at baseline between Cohort I-III and healthy controls.	Genotyping of epilepsy candidate genes at baseline such as genes involved with GABA-ergic, glutamatergic and dopaminergic neurotransmission, GRIN2A/B, CLDN5, PIGA, PIGV, PIGT, ALDH7A1, PNPO, SLC2A1, PDYN, MTHFR, PCDH7, NRG, BDNF, MMP-2/3, TRKB, SV2A, SYNGAP1, SNAP25, HLA-B*15:02, HLA-A*31:01, HLA-A*11:01, CYP2D6, CYP2C9, CYP2C19, UGT1A1, ABCB1, ABCC1, CLCN4, SCN1-3A, SCN8A, KCNA2, KCNT1, KCNQ2/3, KCNJ10, HCN1A, GABRA1, ASIC1a, AQP4, neuropeptide Y.	At baseline between groups (HCs and patients).
Other	Epigenetic changes in Cohort I-III and healthy controls.	Epigenetic mechanisms and regulation of microRNA, TSC1/2, NPRL2/3, DEPDC5, AK3, MECP2, ARX, SCN2/3/8A, KCNQ3, GABRG2, GABRA1, GABRB2/3.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Gut microbial biomarkers for drug treatment response (Cohort II-III).	Identify microbial biomarkers between patients with drug failure vs. patients with no drug failure in Cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Other	Baseline gut microbial biomarkers (Cohort II-III and healthy).	Identify microbial biomarkers between healthy subjects and patients in cohort II-III.	At baseline between groups (HCs and patients) and as change over time from baseline to one years after inclusion for patients in cohort II-III.
Other	Gut microbial signatures between epilepsy subtypes (Cohort II-III).	Identify functional microbial signatures between patients in cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Other	Gut microbial signatures for psychiatric symptoms (Cohort II-III).	Identify functional microbial signatures between patients with and without psychiatric symptoms in cohort II-III.	As change over time from baseline to one year after inclusion for patients in cohort II-III.
Other	Changes from baseline to follow-up in intelligence quotient (IQ) and index scores and cerebral synaptic vesicle glycoprotein 2A (SV2A) binding as imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding and IQ measured as percentage change in Wechsler Adult Intelligence Scale (WAIS-IV) and quantification of binding both globally and in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding in patients with cognitive impairment vs. no cognitive impairment imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding between patients without cognitive impairment vs. patients with cognitive impairment in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to the development of a potential cognitive dysfunction and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding as imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding both globally and in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding between drug failure vs. no drug failure as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with drug failure vs. no drug failure.	As change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding between patients with drug resistance vs. no drug resistance as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with drug resistance vs. no drug resistance.	As change over time from baseline to potential drug resistance and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral [11C]-UCB-J PET SV2A occupancy and arterial spin labeling following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and arterial spin labeling after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral [11C]-UCB-J PET SV2A occupancy and arterial spin labeling following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and arterial spin labeling after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential drug failure and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity following intravenous administration of the ASM levetiracetam (Cohort III and healthy).	Latent variable construct of the [11C]-UCB-J PET SV2A occupancy and resting-state functional connectivity after a levetiracetam displacement paradigm in healthy controls compared with patients.	At baseline between groups (HCs and patients) and as change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding between patients with side effects vs. no side effects as imaged by [11C]-UCB-J PET (Cohort III).	Latent variable construct of [11C]-UCB-J binding and SV2A occupancy in the epileptogenic lesion(s) in patients with side effects vs. no side effects.	As change over time from baseline to potential development of side effects and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral SV2A binding in patients with psychiatric symptoms vs. no psychiatric symptoms imaged by [11C]-UCB-J PET (Cohort III and healthy).	Latent variable construct of [11C]-UCB-J binding between patients without psychiatric symptoms vs. patients with psychiatric symptoms in primary volumes of interest; neocortex, hippocampus, entorhinal cortex, fusiform gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, striatum, anterior cingulate cortex and amygdala in patients from cohort III and healthy controls.	At baseline between groups (HCs and patients) and as change over time from baseline to a potential psychiatric diagnosis and one, three and five years after inclusion for patients in cohort III.
Other	Cerebral [11C]-UCB-J PET SV2A occupancy and the plasma concentration of the ASM levetiracetam (Cohort III and healthy).	Estimation of the occupied SV2A binding sites from the plasma concentration of levetiracetam.	At baseline between groups (HCs and patients).
Other	Hippocampal volume is associated with drug failure (Cohort II-III and healthy).	Structural MRI scans of hippocampus in healthy subjects and patients in cohort II-III.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Other	Volume of thalamus and hippocampus is associated with seizure recurrence (Cohort I-III and healthy).	Structural MRI scans and volume of thalamus and hippocampus.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Cortical thickness is associated with seizure recurrence (Cohort I-III and healthy).	Structural MRI scans of cortical thickness of precentral gyri, parahippocampal cortex, entorhinal and fusiform gyri, precuneus and frontal gyri.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Volume of amygdala is associated with psychiatric symptoms (Cohort I-III and healthy).	Structural MRI scans and volume of amygdala.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Cortical thickness is associated with psychiatric symptoms (Cohort I-III and healthy).	Structural MRI scans and cortical thickness of orbitofrontal cortex.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Within network resting-state functional connectivity (rsfMRI) is associated with seizure recurrence (Cohort I-III and healthy).	Resting-state functional MRI scans and within network connectivity.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Whole-brain structural connectomics is associated with seizure recurrence (Cohort I-III and healthy).	Diffusion Tensor MRI scans and structural connectomics.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Structural connectivity is associated with psychiatric symptoms and drug failure (Cohort I-III and healthy).	Diffusion Tensor MRI scan and structural connectivity between temporal lobe, the limbic system and orbitofrontal cortex (DTI).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	Between network resting-state functional connectivity (rsfMRI) is associated with psychiatric symptoms and drug failure (Cohort I-III and healthy).	Resting-state functional MRI scans and between the anterior cingulate cortex, between prefrontal-limbic systems, angular gyrus, temporal lobe, precuneus, cerebellum, default mode network and executive control network (rsfMRI).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	High density EEG functional connectivity is associated with seizure recurrence (Cohort I-III and healthy).	High density EEG functional connectivity in the theta band.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	High density EEG functional connectivity is associated with psychiatric symptoms (Cohort I-III and healthy).	High density EEG functional connectivity in the anterior cingulate cortex.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Other	High density EEG asymmetry and current source is associated with psychiatric symptoms (Cohort I-III and healthy).	High density EEG and frontal and occipital alpha asymmetry and theta current source density in the anterior cingulate cortex.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Primary	Categorical effect of anti-seizure medication (ASM) on treatment outcome (Cohort II-III).	1) Seizure-free within six months after starting ASM treatment and remained seizure-free for at least one year (last observed seizure within the six months after starting ASM treatment); 2) Seizure-free more than six months after starting ASM treatment and the seizure-free period lasts at least one year; 3) Fluctuations with both seizure-freedom and seizure-relapse; or 4) Never seizure-free for a year at the third- and fifth-year follow-up timepoint.	As change over time from the ASM evaluation period (after 4-7 weeks titration period) to six months, one, three and five years after for patients in cohort II-III.
Primary	Categorical effect of a second seizure/epilepsy diagnosis for patients in Cohort I.	The proportion of patients in Cohort I with one epileptic seizure who become diagnosed with epilepsy.	As change over time of epilepsy diagnosis at six months, one, three and five years after inclusion of patients in Cohort I.
Secondary	Continuous treatment outcome using a seizure severity index (Cohort II-III).	Treatment outcome as percentage change in the Seizure Severity Questionnaire (SSQ).	As a monthly change over time from the ASM evaluation period (after 4-7 weeks titration period) to one, three and five years after for patients in cohort II-III.
Secondary	Continuous treatment outcome rating adverse events (Cohort II-III).	Treatment outcome as percentage change in the Liverpool Adverse Event Profile (LAEP).	As a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III.
Secondary	Continuous treatment outcome rating impression of change (Cohort II-III).	Treatment outcome as percentage change in in Patient's Global Impression of Change (PGIC).	As a monthly change over time from the ASM evaluation period (after 4-7 weeks titration period) to one, three and five years after for patients in cohort II-III.
Secondary	A continuous rating of depression diagnosis (Cohort I-III and healthy).	Percentage change in Major Depression Inventory (MDI).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	A continuous rating of depressive symptoms (Cohort I-III and healthy).	Percentage change in Inventory of Depressive Symptomatology (IDS-SR30).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	A continuous rating of specific depressive symptoms associated with neurological disease (Cohort I-III and healthy).	Percentage change in the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).	At baseline between groups (HCs and patients) and as a monthly change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	Categorical outcome of psychiatric symptoms (Cohort I-III and healthy).	Psychopathology assessed by WHO International Classification of Diseases 10 (ICD-10) diagnostic classification and a semi-structured psychiatric, clinical interview.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	A continuous rating of symptoms of anxiety (Cohort I-III and healthy).	Percentage change in the Generalized Anxiety Disorder 7-item (GAD-7).	At baseline between groups (HCs and patients) and as a monthly change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	Performance in EMOTICOM Emotional Recognition Task (ERT-eyes) (Cohort I-III and healthy).	Differences between healthy controls and patients in recognizing facial expressions and emotions.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	Performance in Rey Auditory Verbal Learning Test (RAVLT) (Cohort I-III and healthy).	Differences between healthy controls and patients in verbal learning and memory.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	Performance in D-KEFS Color-Word Interference Test (Stroop) (Cohort II-III and healthy).	Differences between healthy controls and patients in executive function.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Secondary	Performance in D-KEFS Verbal Fluency (Fluency) (Cohort II-III and healthy).	Differences between healthy controls and patients in executive function.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Secondary	A continuous rating of Wechsler Adult Intelligence Scale (WAIS-IV) (Cohort I-III and healthy).	Differences between healthy controls and patients in IQ and specific index scores measured as percentage change in Wechsler Adult Intelligence Scale (WAIS-IV).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	Performance in Rey Complex Figure Test (RCFT) (Cohort II-III and healthy).	Differences between healthy controls and patients in visio-spatial learning.	At baseline between groups (HCs and patients) and as change over time from baseline to 1, 3 and 5 years after inclusion for patients in cohort II-III.
Secondary	Performance in Boston Naming Test (BNT) (Cohort II-III and healthy).	Differences between patient cohorts in word-retrieval.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Secondary	Performance in Trail Making Test A & B (Trail A & B) (Cohort II-III and healthy).	Differences between patient cohorts in psychomotor speed.	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort II-III.
Secondary	A continuous rating of Quality of Life in Epilepsy (QUOLIE-31) (Cohort I-III and healthy).	Differences between healthy controls and patients in quality of life measured as percentage change in Quality of Life in Epilepsy (QUOLIE-31).	At baseline between groups (HCs and patients) and as change over time from baseline to 1, 3 and 5 years after inclusion for patients in cohort I-III.
Secondary	A continuous rating of Sheehans Disability Score (SDS) (Cohort I-III and healthy).	Differences between healthy controls and patients in quality of life measured as percentage change in Sheehans Disability Score (SDS).	At baseline between groups (HCs and patients) and as change over time from baseline to one, three and five years after inclusion for patients in cohort I-III.
Secondary	A continuous rating of WHO 5 wellbeing index (WHO-5) (Cohort I-III and healthy).	Differences between healthy controls and patients in quality of life measured as percentage change in WHO 5 wellbeing index.	At baseline between groups (HCs and patients) and as a monthly change over time from baseline and one, three and five years after inclusion for patients in cohort II-III.