Presurgical evaluation

People suffering from pharmaco-resistant epilepsy who are considered good candidates for epilepsy surgery undergo extensive evaluations to determine the likelihood that any specific surgical procedure will be effective in controlling seizures without unacceptable adverse effects.

Surgical intervention may be carried out with a high probability of success if different exams have shown two conditions to be true: (a) the area of seizure onset is consistently and repeatedly from the same brain area, such as the frontal or temporal lobe and (b) the implicated region of the brain can be safely removed without creating intolerable deficits.

Up to now, the standard exams normally performed during the presurgical work up include long-term scalp video-EEG, structural and functional neuroimaging, and neuropsychological and psychiatric assessment. If the scalp EEG or neuroimaging data leave doubt regarding the side or precise cortical localization of seizure onset, this noninvasive phase is followed by invasive diagnostics with long-term subdural electrodes or stereotaxic depth electrodes to further define the seizure onset zone and explore surgical possibilities (Zijlmans et al. 2019).

A lot of technological developments in several directions, such as in the field MRI and high-density EEG recordings, may soon, if not already, allow better investigation of the functional and structural alteration at the whole brain. Since focal epilepsy is now known to involve a large-scale network, the understanding of how the epileptogenic tissue connects within the brain network in order to plan optimal surgical strategies is fundamental (Chen et al. 2008; Pittau et al. 2014;

Rosenow and Lüders 2001; Wagner et al. 2011).

In what follows we describe the principles of the different techniques involved in the diagnosis and the pre-surgical planning in epilepsy.

2.1 Long-term scalp video-EEG

Long-term scalp video-EEG recording is a diagnosis technique normally performed for several days or weeks. The main aim is to capture any epileptic activity on the scalp EEG, such as seizures and interictal epileptiform activity. The video recording is important to identify specific movements or behaviors during the seizures (semiology). We will describe in further detail the importance of high-density EEG recordings and the detection of epileptic activity in a later chapter (Chapter 3- EEG).

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2.2 Structural MRI

The most efficient way to discriminate brain tissues and markers of tissue microstructural integrity in the brain is structural MRI (Bernasconi et al. 2019). This technique has become fundamental in the management of drug-resistant epilepsy, as the identification of a clear-cut lesion on structural MRI is associated with favorable seizure outcome after surgery (Jones and Cascino 2016). It has been shown that post-surgical outcome is more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis and less favorable in patients with unremarkable MRI.

Structural MRI can be acquired with different contrasts in order to highlight different types of tissues. In the pre-surgical evaluation, the focus is to find different types of abnormalities: T1-weighted images are used to identify hippocampus sclerosis, atrophy, focal cortical dysplasia and lesions, T2-weighted images are good to visualize edema.

2.3 Functional Imaging

When performing structural brain imaging, one scan is often enough to classify different tissue types and identify structural abnormalities. With functional brain imaging (fMRI) the interest is in evaluating abnormalities in neuronal activity over time, thus images are collected for an extended time period. During an fMRI exam, image volumes are continuously collected with a repetition time (TR) of 2–4 seconds, resulting in a total of 200–300 images for the whole time-series. fMRI uses blood-oxygenation level-dependent (BOLD) contrast to indirectly investigate neuronal activity through the measure of neuronal oxygen consumption and focal perfusion (hemodynamic) changes.

fMRI is therefore mainly used in the context of presurgical evaluation to identify the eloquent cortex such as language areas and the sensory-motor cortex (Baciu et al. 2005).

Simultaneous acquisition of EEG and fMRI allows the combination of high temporal and spatial resolution. This technique is increasingly used for the localization of interictal epileptiform activity (Bénar et al. 2006; Grouiller et al. 2011; Pittau et al. 2012; Vulliemoz et al. 2009; Zijlmans et al. 2007). By correlating the fMRI data with the appearance of epileptic activity in the EEG, it is possible to identify the source of the epileptic discharges, normally consisting of different clusters of activation and de-activation and thereby provide information for improved surgical planning and procedure.

Other functional imaging techniques are also performed to help the localization of the epileptogenic zone, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT). PET and SPECT are based on the intravenous injection of radioactive tracers.

In more detail, PET is useful to detect a focal interictal hypometabolism that can extend beyond

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visible MRI lesions (Chassoux et al. 2010). SPECT is particularly important in focal epilepsy because a decreased cerebral blood flow during interictal periods on a focal area is indicative of the epileptogenic zone and a hyper-perfusion during ictal periods indicates sites of epileptic activity and seizure spread (Van Paesschen et al. 2007). The difference between ictal and interictal SPECT is known as SISCOM (O’Brien et al. 1999).

2.4 Intracranial EEG

If the non-invasive techniques are not sufficient to localize the epileptogenic zone and determine its extension, intracranial recordings might be performed (Chauvel et al. 2019; Diehl and Luders 2000; Zumsteg and Wieser 2000).

There are two types of intracranial EEG electrodes, both implying brain surgery to place them: the stereotactic EEG (sEEG) in which depth electrodes are implanted in the brain, and the subdural EEG or electro-corticogram (ECoG) in which electrodes in grids and/or strips are placed under the dura mater over the brain surface. Both types of electrodes record the local field potentials created by a group of neurons in the proximity of the electrode. The recorded signals normally have high signal-to-noise ratio because they are recorded directly from the cortex without attenuation by the skull.

With this technique, the coverage of the brain is limited at the location of the electrodes and, if the real epileptic zone is not well-targeted, rather the spread of activation than the initial onset could be seen.

2.5 Neuropsychological and Psychiatric assessment

Neuropsychological and psychiatric assessments aim to find cognitive impairments related to epilepsy (Helmstaedter and Witt 2012; Vogt et al. 2017). Up to 80% of the patients already show cognitive decline before epilepsy surgery (Äikiä et al. 1995), and up to 45% of TLE patients may experience a memory decline after surgery (Helmstaedter 2013; Sherman et al. 2011).

Neuropsychological assessments are indicative of the lateralization of different functions, such as language, verbal memory (Mungas et al. 1985) and visuo-spatial memory (Bohbot et al. 1998).

Psychiatric comorbidities, such as affective, obsessive-compulsive disorders and psychoses, are present in 33% of epileptic patients (Kanner 2016) and in these cases there are higher risk for post-operative worsening of the conditions (Foong and Flugel 2007).

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2.6 Predicting surgical outcome

Thanks to the extensive clinical workup in epileptic patients, surgery is likely to obtain seizure-freedom in up to 80% of patients (Baud et al. 2018; Choi et al. 2011; Wiebe et al. 2001).

Unfortunately, in more difficult cases, among others the non-lesional ones, poor outcome after surgery could rates up to 50% with seizures still occurring after the surgery (De Tisi et al. 2011; Yoon et al. 2003). It would, therefore, be beneficial to be able to predict in a patient-specific manner when surgery will or will not work in order to inform patients and better customize therapeutic approaches (van Mierlo et al. 2019; Sinha et al. 2017).

One of the proposed reasons for unsuccessful surgical resections is the notion that even focal epilepsies are diseases of abnormal network organization of brain areas and the connections between them (Bragin et al. 2000; Kramer and Cash 2012; Spencer 2002). Connectivity and network analysis are good candidate tools for improving the diagnosis of epilepsy and classification in the absence of visible EEG abnormalities (van Mierlo et al. 2019; Verhoeven et al. 2018). It has been already shown that connectivity could predict the diagnosis of epilepsy with sensitivity of 51% and specificity of 73% (Douw et al. 2010b) and an increased theta band connectivity revealed in magnetoencephalography could be potentially used as a biomarker for tumor-related epilepsy (Douw et al. 2010a). Furthermore, graph theory measures in intracranial studies (Lagarde et al.

2018; Van Mierlo et al. 2013; Wilke et al. 2011) as well as EEG/MEG studies have been used as quantitative measures of the epileptogenic zone and to evaluate their relations with the actually resected brain tissue or the post-surgical seizure control.

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