POPULATION
Patients will be recruited starting November 2019 to November 2021 at the Inselspital Bern, Hôpitaux Universitaires de Genève, Universitätsspital Zürich, Universitätsspital Basel, Kantonsspital St.Gallen, Kantonsspital Aarau and Ospedale Civico Lugano. Healthy controls will be recruited at the Inselspital Bern and in the Hôpitaux Universitaires de Genève. Patients and healthy controls sign informed consent that allows usage of clinical information, images and follow-up consultations. All sites received approval by their respective cantonal ethics committee in accordance with the declaration of Helsinki. Clinical decision making in diagnostics and therapy will be done independently from the study. Central quantitative data evaluation will be performed on pseudonymized data only.
Adult patients, who present themselves for the first time at the emergency department because of a possible epileptic seizure, who sign informed consent, will be included in this study. EEG and MRI will be executed if possible the same day, but no later than seven days after the possible seizure. Exclusion criteria are
history of unprovoked seizure,
history of provoked seizure within the previous four weeks,
inability to perform MRI or EEG,
present alcohol dependency and drug abuse.
If EEG suggests presence of generalized epilepsy, which does not require MRI, it will be offered through the grant, in order to determine if our tools are capable to differentiate between focal and generalized epilepsy conditions.
Matched controls will be selected by the same criteria, adding only that they shall not have an underlying neurologic or psychiatric disease.
All data will be pseudoanonymized before postprocessing.
SPIKE MAPS AND MICROSTATES
EEGs, obtained as soon as possible after the first event, i.e. within 24-72 h, will be evaluated in a first step conventionally and then quantitatively. We then will focus on the detailed analysis of microstates during resting EEG, analyze the resting states and compare the results with the control group. Microstates are considered stable topographies on a subsecond temporal scale and have been used to describe the EEG in a number of pathologies.
These basic EEG microstates represent quasi stable topographies, which can be described by their frequency of occurrence, duration or also their syntax. Interestingly, the basic microstates are quite resistant to anesthesia or sleep, which makes them a particular interesting marker of abnormal brain activity.
We will construct a “spike map” using publicly available software like cartool (brainmapping.unige.ch/cartool). Next to visual identification of the IEDs, we will use software to detect them in the EEG and construct the spike topography.
For EEGs without IEDs, in a second step, we aim to develop a library of possible foci (corresponding to 28 or more cortex areas), for which possible pathological microstates are simulated.
This requires the use of advanced head models to estimate the spike morphology at the scalp level from sources within cortical areas. The EEGs are then screened if one or more of these pathological microstates are present and point to an epileptogenic underlying process.
FUNCTIONAL CONNECTIVITY
From the resting EEG we will extract the whole brain directed functional connectome, first constructing a patient specific head model, then parcelling the grey matter into 82 regions of interests (ROIs). We will identify which anatomic structures show altered functional connectivity compared to healthy controls.
Directed functional connectivity (DFC) reveals the causal influence of one signal (coming from a distinct region) onto another signal/region within a dedicated network and among different networks. It determines directional relationships between activities of different brain regions and reflects short- and long-range interactions of complex dynamic subsystems that enable information flow through the human brain. Directed functional connectivity applied to brain sources, namely source space DFC, revealed, even in the absence of interictal spikes and seizures, significant connectivity differences in TLE compared to healthy controls based on source space DFC during resting state recorded with high-density EEG, suggesting that DFC measures could serve as a qualitative parameter to determine if the person suffers from underlying epilepsy or not, and therefore if the first seizure needs to be treated or not.
ADVANCED NEUROIMAGING
All images will be screened for structural epileptogenic lesion and incidental findings using a dedicated epilepsy protocol following the guidelines of the ILAE. Diffusion and perfusion MRI is performed to identify potentially transient peri-ictal abnormalities and their lateralizing value. With the adaptations in MRI first seizure protocols, we intend to detect possibly all epileptogenic lesions.
Centralized reading of all data will be performed at the Support Center of Advanced Neuroimaging (SCAN), Institute of Diagnostic and Interventional Neuroradiology at the University of Bern. The raters will be pre-informed by patient history, clinical and EEG findings and will adhere to a predefined definition of epileptogenic vs. non-epileptogenic lesions by entity.
AUTOMATIC MORPHOMETRY
Large scale structural alterations and networks
Cortical and subcortical brain areas will be automatically parcellated using the T1 image and the freely available software FreeSurfer. It distinguishes grey matter, white matter, blood vessels, ventricles and scull and measures volumes and other morphometric parameters like cortical thickness, surface area or curvature. These will be compared to their respective regional normative values, correcting for age, sex, MR scanner and MR sequence. A similar procedure was already performed in the ENIGMA study for epilepsy, which showed patterns of atrophy for every subtype of epilepsy. Now we will investigate, whether these patterns of atrophy are already detectable earlier in the progress of disease, namely after the first seizure and if this pattern already allows a classification shortly after manifestation.
NEURAL CURRENT IMAGING
A newly developed MR sequence (spin locking effects) will be applied to investigate non-hemodynamic field effects related to epileptic activity. A first technical report of effects on magnetic field perturbations in a small series of patients that underwent presurgical phase II workup reported a hemispheric concordance in seven of eight patients. We will investigate, whether this new sequence generates reproducible effects in patients after a first seizure and if these findings can support the diagnosis of epilepsy after the first seizure.
MULTIOMICS A.I
Two years after the first seizure, patients will be followed up and relapse(s) of the event will be ascertained.
Information from advanced neuroimaging, spike maps, functional connectivity, automatic morphometry and spin-locking effects will flow into an artificial intelligence algorithm that shall dichotomize the possible seizures into epileptic or not. Further, it shall determine the probability of seizure recurrence. Retrospectively, we expect to evaluate whether there were hints already available after the first seizure that would have suggested higher seizure recurrence probability and rank their diagnostic significance.
