# The role of SEEG in the presurgical decision-making process in MRI-normal mesial temporal lobe epilepsy

H. Catenoix, K. Decaestecker, M. Hermier, M. Chochoi, V. Guinet, A.

Montavont, J. Isnard, S. Boulogne, W. Szurhaj, C. Haegelen, et al.

► To cite this version:

H. Catenoix, K. Decaestecker, M. Hermier, M. Chochoi, V. Guinet, et al. The role of SEEG in the presurgical decision-making process in MRI-normal mesial temporal lobe epilepsy. Revue Neurologique, 2024, 180 (10), pp.1128-1138. 10.1016/j.neurol.2024.06.006. hal-04985450

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Original article

# The role of SEEG in the presurgical decision-making process in MRI-normal mesial temporal lobe epilepsy

<figure><img src="image_3.png" /></figure>

H. Catenoix<sup>a,b,*</sup>, K. Decaestecker<sup>c</sup>, M. Hermier<sup>d</sup>, M. Chochoi<sup>e</sup>, V. Guinet<sup>a,b</sup>, A. Montavont<sup>a,b</sup>, J. Isnard<sup>a,b</sup>, S. Boulogne<sup>a,b</sup>, W. Szurhaj<sup>f</sup>, C. Haegelen<sup>b,g</sup>, N. Reyns<sup>h</sup>, M. Guenot<sup>b,g</sup>, P. Derambure<sup>e</sup>, J. Jung<sup>a,b,1</sup>, S. Rheims<sup>a,b,1</sup>

INFO ARTICLE

Article history:

Received 8 February 2024

Received in revised form

6 May 2024

Accepted 20 June 2024

Available online 29 August 2024

Keywords:

Epilepsy

SEEG

Hippocampus

Surgery

ABSTRACT

Objectives. – In patients with mesial temporal lobe epilepsy (mTLE) and normal MRI, anterior temporal lobectomy sparing the hippocampus might be considered because of the risk of post-operative memory deficit. However, it is unclear whether some patients with normal MRI and non-invasive EEG and semiological pattern highly suggestive of mesial temporal seizures demonstrate a seizure onset network sparing the hippocampus, potentially warranting surgery.

Methods. – A retrospective study of 17 patients with mTLE epilepsy and normal MRI who underwent SEEG. Only patients whose non-invasive presurgical data suggested an unilateral mesial temporal epileptogenic zone (EZ), as defined by combination of ictal semiology and ictal EEG during scalp video-EEG, were included. SEEG data were analyzed using both visual and quantitative approaches. Two EZ organization were defined: (i) EZ involved the hippocampus at the onset of the ictal discharge (HIP group); (ii) patients in whom a delay > 1 sec was observed between the seizure onset and the involvement of the hippocampus (nHIP group). Non-invasive clinical and functional imaging data, as well as post-operative outcomes, were compared across groups.

Results. – Eleven patients were included in HIP group and 6 in the nHIP group. In the nHIP group, the maximal epileptogenicity was in the amygdala in five patients and in the entorhinal cortex in one. The hippocampus normalized interictal spiking activity was

<footnote><sup>a</sup>Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Lyon 1 University, Lyon, France</footnote>

<footnote><sup>b</sup>Lyon Neuroscience Research Center, Inserm U1028, CNRS UMR5292, Lyon 1 University, Lyon, France</footnote>

<footnote><sup>c</sup>Departement of Neurology, General Hospital, Valenciennes, France</footnote>

<footnote><sup>d</sup>Department of Neuroradiology, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote><sup>e</sup>Department of Clinical Neurophysiology, Lille University Medical Center and EA 1046, University of Lille2, Lille, France</footnote>

<footnote><sup>f</sup>Department of Clinical Neurophysiology, Amiens University Medical Center, Amiens, France</footnote>

<footnote><sup>g</sup>Department of Functional Neurosurgery, Hospices Civils de Lyon and Lyon 1 University, Lyon, France</footnote>

<footnote><sup>h</sup>Department of Neurosurgery and Neurooncology, Lille University Roger Salengro Hospital, Lille, France</footnote>

<footnote>* Corresponding author at: Department of Functional Neurology and Epileptology, 59, boulevard Pinel, 69677 Bron Cedex, France. E-mail address: helene.catenoix@chu-lyon.fr (H. Catenoix).</footnote>

<footnote n="1">¹ These authors contributed equally to this work.</footnote>

<footnote>https://doi.org/10.1016/j.neurol.2024.06.006</footnote>

<footnote>0035-3787/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>
not different between groups. None of the patients characteristics collected during the non-invasive presurgical workup was associated with the SEEG-based organization of the EZ. Twelve patients underwent a surgical resection, including temporal cortectomy sparing hippocampus in six. Seizure and neuropsychological post-operative outcomes were similar. Conclusion. – In patients with MRI-normal mTLE, SEEG should be included in the surgical decision-making process because seizure organization cannot be predicted from non-invasive investigations. When hippocampus is not included in the EZ, temporal resection sparing the hippocampus can be considered.

© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

# 1. Introduction

Mesial temporal lobe epilepsy (mTLE) is a well-defined entity, having clinical and radiological characteristics such as evidence of hippocampal sclerosis on magnetic resonance imaging (MRI), for which epilepsy surgery was proven to be efficient [1,2]. Nonetheless, it has been repeatedly demonstrated that the absence of abnormal findings on MRI should not preclude a presurgical evaluation in patients with suspected mTLE, as encouraging long-term postoperative seizure outcomes are attainable [3]. However, in these patients, the issue of cognitive post-operative outcome is of great importance, particularly when the epilepsy is lateralized within the dominant hemisphere. In the absence of structural abnormality of the hippocampus on MRI, the risk of severe post-operative verbal memory deficit following hippocampal resection in the dominant hemisphere is high and might result either to contraindicate epilepsy surgery or to propose a more circumscribed resection, sparing the hippocampus. However, the validity of this approach remains a matter of debate, due to the risk of poor seizure outcome [4].

In patients with non-lesional TLE, it is common that seizure onset exclusively originate from mesial temporal structures, without early neocortical involvement [5]. In such cases, a surgery that respects the integrity of the hippocampus may not yield the expected effectiveness. On the other hand, other subtypes of TLE have also been well characterized, including seizures originating in the temporal pole [6], latero-mesial or lateral temporal lobe seizures [7]. Some semiological features may help to disentangle seizures originating from mesial temporal lobe and lateral temporal seizures, such as abnormal epigastric sensation and early oral automatisms in mesial temporal seizures and sensory hallucinations in lateral temporal lobe seizures [7,8]. However, it is unclear whether some patients with normal MRI and non-invasive EEG and semiological pattern highly suggestive of mesial temporal seizures might still demonstrate a seizure onset network sparing the hippocampus during stereoelectroencephalography (SEEG), raising two important issues: (i) is there a rationale to perform SEEG in patients with normal MRI and typical mTLE electro-clinical semiology, with the objective to discuss temporal lobectomy sparing the hippocampus? and (ii) which SEEG criteria might be used to guide the surgical decision?

To address these issues, we analyzed the data of 17 patients with mTLE epilepsy and normal MRI who underwent SEEG, with the objective of defining criteria, obtained either with non-invasive investigations or SEEG, which can help the decision-making process concerning surgical intervention.

# 2. Material and methods

## 2.1. Study design

This study is a retrospective study conducted in two French tertiary epilepsy centers (Lyon and Lille). The study was approved by the ethics committee of Hospices Civils de Lyon.

## 2.2. Patient selection

We reviewed medical records of patients who had intracerebral EEG recordings with SEEG as part of their presurgical evaluation between 2010 and 2020 at the Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France or at the Department of Clinical Neurophysiology, Lille University Hospital, Lille, France to identify those who fulfilled the following criteria: (i) adult (age - > 18 years) patients; (ii) drug-resistant TLE; (iii) normal brain MRI; (iv) non-invasive presurgical data suggesting an unilateral mesial temporal epileptogenic zone (EZ), as defined by combination of ictal semiology and ictal EEG captured during scalp video-EEG (fig. 1):

* ictal semiology: epigastric sensation and/or fear and/or déjà-vu followed by oro-alimentary and elementary upper limb automatisms and delayed loss of contact [7]. Ictal scalp EEG: unilateral occurrence of a low-voltage fast (beta) activity or of a well-localized flattening, or (in the absence of the two previous patterns) by the occurrence of a rhythmic theta activity localized over the temporal lobe (T4/T3; F9/10, T9/10 electrodes).

Patients with clinical semiology suggesting initial involvement of the lateral temporal neocortex (initial auditory illusion or hallucination) [7] or the temporal pole (initial loss of contact) [6] or temporal plus seizures (initial auditory illusion or rotatory vertigo, Ipsilateral tonic motor signs or contralateral versive manifestations) [9] were excluded.
<figure><img src="image_4.png" /><figcaption>Fig. 1 – Flow chart describing the selection process and seizure outcome according to the type of surgery.</figcaption></figure>

Patient with seizures arising independently from the two temporal lobes were also excluded (but contralateral temporal lobe propagation was observed for some patients).

Overall, among the 456 patients who had undergone SEEG between 2010 and 2020, 17 fulfilled the inclusion criteria and contributed to the present study.

## 2.3. Non-invasive presurgical evaluation

All patients underwent a non-invasive presurgical epilepsy workup, in which the detailed medical history was collected and a neurological examination was performed, as well as long-term scalp video-EEG monitoring, 3T MRI, interictal ¹⁸Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and neuropsychological testing. Some patients also underwent magnetic source imaging.

All non-invasive data, including seizures captured during the video-EEG and the MRI, were reviewed by three clinical experts (HC, JJ, SR). All MRI were also independently reviewed by a neuroradiologist (MH), blinded to other data, to confirm the absence of focal brain lesion, especially hippocampal atrophy and/or abnormal signal intensity of the mesial temporal structures on T2-wheigted and FLAIR sequences. No post-processing analysis of MRI data was performed.

## 2.4. SEEG recordings

Decision to perform SEEG was made at an individual patient level after a detailed review of the non-invasive data during multidisciplinary epilepsy surgery meeting. Eight to 14

electrodes (5-18 contacts, diameter = 0.8 mm, 1.5 mm apart, Dixi, Besançon, France) were implanted per patient, according to Talairach's stereotactic methodology or, after 2014, using a frameless stereotactic surgical robot. Electrode location was verified using either post-implantation MRI or post-implantation computed tomography coregistered with preoperative MRI using dedicated in-house software (IntrAnat, https://f-tract.eu/software/intranat/). The anatomical targets of electrodes were established in each patient, with the primary objective to assess the involvement of the hippocampus or other temporo-mesial structures at seizure onset. Accordingly, anterior hippocampus was explored in all patients. In 12 patients, another electrode also sampled the posterior part of the hippocampus, and exploration was bilateral in eight (in case of secondary contralateral propagation of scalp EEG discharges during non-invasive recordings). The localization of SEEG contacts are detailed in supplemental Table 1.

SEEG data were recorded continuously using a 128 or 256-channels video-EEG monitoring system (Micromed, Treviso, Italy) with a sampling rate of 256 Hz during interictal periods and seizures. The reference electrode was chosen for each patient on an implanted contact, located in the white matter. High- (50 Hz) and low-frequency (1 Hz) direct electrical cortical stimulations were performed aiming to map cortical function, recording after discharges, and inducing habitual seizures.

## 2.5. SEEG signal analysis

SEEG data were analyzed using both visual and quantitative approaches. For visual analysis, SEEG data were band-pass
filtered at 0.53–100 Hz whereas for quantitative SEEG signal analysis, no filter was applied. All SEEG signals were referenced using bipolar montage between neighboring contacts of the same electrode. To make comparisons across patients, quantitative analyses were performed in seven anatomical regions of interest: anterior hippocampus, amygdala, entorhinal cortex, temporal pole, first temporal gyrus, second temporal gyrus, insula.

### 2.5.1. *Interictal data*

A 20-min bipolar interictal recording was selected that fulfilled the following criteria: (1) recorded in a restful, non-sleep state between 8 a.m. and 2 p.m.; (2) not artifact degraded; (3) at least 2 h following or preceding a seizure; and (4) at least 48 h after electrode implantation. The first available segment that fulfilled these criteria was chosen for analysis. Spike rates per bi-polar channel were calculated in Anywave software (https://meg.univ-amu.fr/wiki/AnyWave) using Delphos plug-in (Detector of ElectroPhysiological Oscillations and Spikes) which automatically detects spikes based on the ZHO method [10,11]. After having computed the mean spikes rate, the spiking activity of each region of interest was normalized relatively to the brain region with highest spiking activity (ratio of spiking activity).

Because SEEG recordings with sampling rate (above 1000 Hz) were not available, we were unable to analyze inter-ictal high frequency oscillations.

### 2.5.2. *Ictal data*

2.5.2.1. **Visual analysis.** Seizure data were collected and visually analyzed, with special attention to the seizure-onset patterns, and to the structures involved at seizure onset, particularly the temporo-mesial structures. First, we defined seizure onset as the earliest time at which SEEG activity evolved to one of the typical seizure onset patterns described by Lagarde et al. [12] for one or several bipolar contacts prior or concomitantly to clinical ictal symptoms. The region of interest involved at first was defined at the seizure-onset zone and the time of involvement of the other regions of interest was estimated visually. Secondly, we estimated the time delay (in seconds) between involvement of hippocampus and the seizure-onset zone.

2.5.2.2. **Quantitative analysis.** The Epileptogenicity Index (EI) was calculated for all seizures using the Anywave Software (available at https://meg.univ-amu.fr/wiki/AnyWave:Plugin_EI). The EI is a semiautomated method to quantify the epileptogenicity of different brain structures using SEEG signals [13]. EI combines the ratio of fast frequencies (beta/gamma) relative to slower frequencies and the time of involvement of each region. The EI is a normalized value that ranges from 0 (no epileptogenicity) to 1 (peak epileptogenicity) in the selected channels. The median EI for each channel across all seizures for an individual patient was calculated. As proposed previously EZ [14], epileptogenic channels were defined as those with an EI > 0.4.

2.5.2.3. **EZ organization.** We defined the EZ organization in respect with the involvement of the hippocampus during the course of the seizure. Based on the delay measured by visual

analysis between the seizure onset and the involvement of hippocampus, we separated patients in two groups:

* group #1: patients in whom the structures involved at the onset of the ictal discharge included the hippocampus (HIP group);

* group #2: patients in whom a delay > 1 sec was observed between the seizure onset and the involvement of the hippocampus (nHIP group). In the 12 patients whose hippocampus was sampled with two electrodes (anterior and posterior), we considered the electrode where the earliest involvement by the ictal discharge was observed.

## 2.6. Surgery and post-operative follow-up

Eligibility for surgery was collegially decided during a dedicated epilepsy surgery meeting after detailed review of non-invasive and SEEG data. For each individual patients, the chance of seizure freedom was balanced with the risk of disabling post-operative memory deficit. Accordingly, the discussion could lead to three different decisions: (i) no surgery if the surgical approach required to achieve reasonable chance of seizure freedom was considered to be at too high risk of inducing disabling post-operative memory deficit; (ii) conventional anterior temporal lobectomy (ATL); (iii) temporal resection sparing the hippocampus (TRsH) when available data were judged strong enough to consider extra-hippocampus seizure onset or, even if this decision reduced the chance of surgical success, when the risk of disabling post-operative memory deficit was considered too high to propose resection of the hippocampus. The surgical procedure was similar in all patients undergoing TRsH, with resection of the temporal pole (3-4 cm), complete resection of the amygdala and the uncus, ablation of the anterior part (2 cm) of the parahippocampal gyrus. The totality of hippocampus, including its head, was spared.

Post-operative follow-up assessed seizure outcome using the Engel scale [15]. Post-operative neuropsychological evaluation was performed after a minimum post-operative follow-up of 1 year in all patients.

## 2.7. Statistical analysis

Analyses were performed to assess the relation between the SEEG-defined EZ organization and:

* all other data collected during SEEG (ictal and inter-ictal): EI, spiking activity and results of direct electrical stimulations;

* the non-invasive clinical data:

* age, gender, age at epilepsy onset, epilepsy duration,

* results of neuropsychological evaluation: normal, deficit in verbal episodic memory or visuo-spatial episodic memory or both,

* result of 18F-FDG-PET: normal, hypometabolism limited to the mesial temporal structures, limited to temporal neocortex, or involving both mesial temporal structures and temporal neocortex;

* with the post-operative seizure outcome in the subgroup of patients who underwent epilepsy surgery. In these later, we assessed the relation between EZ organization, Engel class 1
outcome and the type of surgery (ATL or TRsH) as well as evolution of neuropsychological status (no change – improvement – aggravation).

For all analyses, we used Mann-Whitney U-tests for quantitative variables and Fisher exact test for categorical variables. The threshold of significance was set at a P-value below 0.05. All statistical tests were performed with the R statistical software.

# 3. Results

## 3.1. Patient characteristics

Seventeen patients (6 males and 11 females) were included in this study (Table 1). The mean (±SD) age was 33.5 years ± 8.7 and the mean (±SD) age at epilepsy onset was 18.4 years ± 11. A total of 15 patients were right-handed and two were left-handed. All patients had typical ictal semiology involving mesial temporal structures, but there were some interindividual differences: three patients had no aura prior to their ictal event while 14 patients had either psychic or abdominal auras. Nine patients had normal memory on neuropsychological testing while 8 patients disclosed delayed memory impairment. FDG-PET showed normal temporal metabolism in three patients, mesial temporal hypometabolism in nine, and exclusively temporo-polar or lateral temporal hypometabolism in five. The patient characteristics are presented in Table 1.

## 3.2. SEEG-based organization of the epileptogenic zone

Forty seizures were analyzed ([mean ± SD] 2.35 ± 0.25 per patient) using both visual and quantitative analysis of SEEG signals. For each patient, the ictal pattern was reproducible (Table 2).

### 3.2.1. Visual analysis of SEEG signals

Based on visual analysis of SEEG signals, we observed two patterns of EZ organization. In a first group of 11 patients (64.7%, HIP group), seizures onset involved immediately temporo-mesial structures including hippocampus. Ictal activity remained confined to mesial structures or propagated secondarily to insula and temporal neocortex, rarely to frontal region or contralateral temporal lobe. Electrical stimulation of the hippocampus using the routine clinical procedure (performed in 10 patients) triggered typical seizures in nine cases.

In a second group of six patients (35.3%, nHIP group), seizure onset was located in the temporal pole or in the amygdala, with a delayed propagation to ipsilateral hippocampus of 3 to 10 seconds, as illustrated in fig. 2. Ictal activity also spread to insula, neocortex temporal or frontal region. Electrical stimulation of the hippocampus at 1 Hz never induced typical seizures.

### 3.2.2. Quantitative analysis of SEEG signals

In the HIP group, the EI in hippocampus was > 0.4 in 10 patients (91%), with a single patient with EI in the hippocampus at 0.3. The normalized interictal spiking activity of

hippocampus was equal to 1 for 5/11 patients, showing that hippocampus was the structure having the highest spiking rate. For the six other patients, the maximal interictal spiking activity was observed in temporal pole (3), amygdala (2) and entorhinal cortex (1).

In the nHIP group, hippocampus EI was always < 0.4 (6/6). The EI was > 0.4 in the amygdala in five of the six patients and in the entorhinal cortex in one. The hippocampus was the structure with the highest spiking rate in two patients, whereas for the four others, the normalized interictal spiking activity was maximal in the amygdala (n = 2), entorhinal cortex (n = 1) and temporal pole (n = 2).

The proportion of patients with hippocampal epileptogenic EI (EI > 0.4) was higher in the HIP group than in the nHIP group (91% vs. 0%, P < 0.001). In contrast, the normalized interictal spiking activity of hippocampus was not different between HIP and nHIP group.

## 3.3. Relation between EZ organization and clinical characteristics

Overall, none of the patients characteristics collected during the non-invasive presurgical workup was associated with the SEEG-based organization of the EZ (Table 3). Age of patients, gender, age at epilepsy onset, epilepsy duration, presence of secondary generalization did not differ between the HIP group and the nHIP group. Similarly, the rate of verbal or visual memory deficits and the spatial distribution of PET hypometabolism in medial temporal lobe structures was not different between the HIP group and the nHIP group.

## 3.4. Relation between EZ organization and surgical outcome

A total of 12 patients (70%) underwent a surgical resection following SEEG. The mean (±SD) age at surgery was 34.6 years ± 10.6 (Table 4). The mean (±SD) duration of epilepsy at surgery was 14.5 years ± 11.4. The mean (±SD) follow-up after surgery was 76 months ± 40, with a minimum duration of follow-up of one year (fig. 1 and Table 3).

Surgical treatment was contraindicated in five patients due to a functional risk (risk of verbal memory deficit following surgery). Based on SEEG data, conventional ATL was performed in six patients, including four patients belonging to the HIP group, whereas the remaining six patients underwent temporal cortectomy sparing hippocampus, including four with nHIP EZ organization. Among the twelve patients whose EZ was in the language dominant hemisphere, only six underwent surgery, including four for whom a resection sparing the hippocampus was performed.

Overall, 8/12 patients (67%) had favorable outcome following the surgery (Engel I class outcome) whereas 4/12 were not seizure free. Specifically, four of the six patients (66%) who underwent conventional ATL and four (66%) of those who underwent Temporal cortectomy sparing hippocampus achieved Engel class I outcome.

Surgical procedure was not homogeneous, in respect to the EZ organization. In the HIP group six of the eleven patients underwent epilepsy surgery. The procedure consisted in conventional ATL in four patients, with 3 patients Engel class
<table><caption>Table 1 - Clinical and para-clinical data.</caption><thead><tr><th></th><th>Gender, Age</th><th>Epilepsy onset (years)</th><th>Handedness</th><th>Past history</th><th>Delayed Memory deficit</th><th>FDG-PET temporal hypometabolism</th><th>Ictal semiology</th><th>EEG ictal</th><th>Focal Bilateral Tonic Clonic Seizures</th></tr></thead><tbody><tr><td>1</td><td>F, 23</td><td>9</td><td>R</td><td>Post-vaccination seizures in infancy</td><td>No</td><td>No</td><td>Déjà-vu sensation, oroalimentary and gestual automatisms, epigastric aura, psychic hallucinations, chills, heat sensation</td><td>L theta temporal and then bi-temporal discharge</td><td>Frequent</td></tr><tr><td>2</td><td>M, 42</td><td>19</td><td>R</td><td>-</td><td>No</td><td>Mesial</td><td>Epigastric aura, heat sensation, sweat, loss of consciousness, speech disturbances</td><td>L theta anterior temporal discharge</td><td>Rare</td></tr><tr><td>3</td><td>M, 30</td><td>11</td><td>R</td><td>-</td><td>No</td><td>Mesial</td><td>Oroalimentary and gestual automatisms, loss of consciousness, speech disturbances</td><td>L spikes and theta temporal discharge</td><td>No</td></tr><tr><td>4</td><td>M, 33</td><td>12</td><td>R</td><td>-</td><td>Visual</td><td>Mesial and polar</td><td>Dreamy state, oroalimentary automatisms, loss of consciousness, mutism, speech disturbances</td><td>L temporal spikes, focal fast activity and anterior temporal discharge</td><td>Rare</td></tr><tr><td>5</td><td>F, 28</td><td>12</td><td>R</td><td>-</td><td>No</td><td>Mesial and lateral</td><td>Heat sensation, psychic hallucinations, gestual automatisms, speech disturbances</td><td>L postero-anterior temporal discharge</td><td>Rare</td></tr><tr><td>6</td><td>M, 38</td><td>4</td><td>R</td><td>-</td><td>Verbal</td><td>Mesial and lateral</td><td>Psychic hallucinations, oroalimentary and gestual automatisms, loss of consciousness</td><td>L temporal discharge</td><td>No</td></tr><tr><td>7</td><td>M, 36</td><td>31</td><td>R</td><td>-</td><td>No</td><td>No</td><td>Heat sensation, epigastric aura, psychic hallucinations, oroalimentary and gestual automatisms</td><td>L theta posterior temporal discharge</td><td>No</td></tr><tr><td>8</td><td>F, 28</td><td>20</td><td>L</td><td>-</td><td>Verbal</td><td>Mesial and polar</td><td>Deja vu sensation, oroalimentary automatisms, loss of consciousness, speech disturbance</td><td>L anterior temporal discharge</td><td>Rare</td></tr><tr><td>9</td><td>F, 44</td><td>33</td><td>R</td><td>-</td><td>No</td><td>Mesial and polar</td><td>Heat sensation, epigastric aura, oroalimentary and gestual automatisms, epigastric aura, loss of consciousness</td><td>Focal fast activity, R postero-anterior temporal discharge</td><td>Rare</td></tr><tr><td>10</td><td>F, 39</td><td>15</td><td>R</td><td>Head trauma at 12 years</td><td>Verbal and visual</td><td>Polar and lateral</td><td>Heat sensation, epigastric aura, gestual automatisms, loss of consciousness</td><td>Focal fast activity, R temporal discharge</td><td>No</td></tr><tr><td>11</td><td>F, 43</td><td>40</td><td>L</td><td>-</td><td>No</td><td>Polar and lateral</td><td>Oroalimentary and gestual automatisms, loss of consciousness</td><td>L theta temporal and then bi-temporal discharge</td><td>Rare</td></tr><tr><td>12</td><td>M, 25</td><td>6</td><td>R</td><td>-</td><td>Verbal</td><td>Mesial</td><td>Epigastric aura, oroalimentary and gestual automatisms, loss of consciousness</td><td>R fronto-temporal discharge</td><td>No</td></tr><tr><td>13</td><td>F, 49</td><td>39</td><td>R</td><td>-</td><td>No</td><td>No</td><td>Oroalimentary and gestual automatisms, loss of consciousness</td><td>R temporal discharge</td><td>Frequent</td></tr></tbody></table>
<table><caption>Table 1 (Continued)</caption><thead><tr><th></th><th>Gender, Age</th><th>Epilepsy onset (years)</th><th>Handedness</th><th>Past history</th><th>Delayed Memory deficit</th><th>FDG-PET temporal hypometabolism</th><th>Ictal semiology</th><th>EEG ictal</th><th>Focal Bilateral Tonic Clonic Seizures</th></tr></thead><tbody><tr><td>14</td><td>F, 38</td><td>13</td><td>R</td><td>-</td><td>Verbal and visual</td><td>Mesial</td><td>Epigastric aura, psychic hallucinations, oroalimentary and gestual automatisms, loss of consciousness, speech disturbance</td><td>L spikes posterior temporal discharge</td><td>No</td></tr><tr><td>15</td><td>F, 35</td><td>23</td><td>R</td><td>-</td><td>Verbal</td><td>Polar</td><td>Heat sensation, epigastric aura, oroalimentary and gestual automatisms, loss of consciousness, speech disturbances</td><td>L temporal and then bi-temporal discharge</td><td>Rare</td></tr><tr><td>16</td><td>F, 21</td><td>3</td><td>R</td><td>-</td><td>No</td><td>Polar</td><td>Epigastric aura, psychic hallucinations, oroalimentary and gestual automatisms</td><td>R anterior temporal discharge</td><td>No</td></tr><tr><td>17</td><td>F, 27</td><td>22</td><td>R</td><td>-</td><td>Verbal and visual</td><td>Polar</td><td>Psychic hallucinations, oroalimentary and gestual automatisms</td><td>R temporal discharge</td><td>No</td></tr></tbody></table>

R: Right, L: Left.

<table><caption>Table 2 – SEEG and surgical data.</caption><thead><tr><th></th><th>No. and side of SEEG electrodes</th><th>Interictal activity in hippocampus (ratio)</th><th>EEG ictal in hippocampus</th><th>Seizures (number)</th><th>Delay of hippocampus epileptic discharge (sec)</th><th>EI in hippocampus</th><th>Typical Seizure elicited by hippocampal stimulation</th></tr></thead><tbody><tr><td>1</td><td>12 L, 2 R</td><td>0,56</td><td>Focal LVFA</td><td>3</td><td>No delay</td><td>1</td><td>Yes</td></tr><tr><td>2</td><td>9 L, 1 R</td><td>1,00</td><td>Focal LVFA</td><td>2</td><td>No delay</td><td>0,55</td><td>Yes</td></tr><tr><td>3</td><td>8 L, 1 R</td><td>0,88</td><td>Focal rythmic spiking</td><td>6</td><td>No delay</td><td>0,9</td><td>Yes</td></tr><tr><td>4</td><td>11 L, 2 R</td><td>0,17</td><td>Focal LVFA</td><td>4</td><td>8</td><td>0</td><td>NA</td></tr><tr><td>5</td><td>8 L</td><td>1,00</td><td>Focal LVFA</td><td>1</td><td>No delay</td><td>1</td><td>Yes</td></tr><tr><td>6</td><td>10 L</td><td>0,68</td><td>Focal LVFA</td><td>2</td><td>4</td><td>0,2</td><td>NA</td></tr><tr><td>7</td><td>12 L, 2 R</td><td>0,21</td><td>Focal rythmic spiking</td><td>1</td><td>No delay</td><td>1</td><td>Yes</td></tr><tr><td>8</td><td>8 L</td><td>0,33</td><td>Focal rythmic spiking</td><td>1</td><td>No delay</td><td>0,3</td><td>NA</td></tr><tr><td>9</td><td>9 R</td><td>0,16</td><td>Focal LVFA</td><td>2</td><td>10</td><td>0,2</td><td>No</td></tr><tr><td>10</td><td>8 R</td><td>1,00</td><td>Focal LVFA</td><td>2</td><td>No delay</td><td>1</td><td>Yes</td></tr><tr><td>11</td><td>10 L, 3 R</td><td>0,09</td><td>Focal rythmic spiking</td><td>2</td><td>No delay</td><td>1</td><td>No</td></tr><tr><td>12</td><td>13 R</td><td>1,00</td><td>Focal LVFA</td><td>2</td><td>8</td><td>0,1</td><td>NA</td></tr><tr><td>13</td><td>12 R, 1 L</td><td>1,00</td><td>Focal LVFA</td><td>3</td><td>No delay</td><td>1</td><td>Yes</td></tr><tr><td>14</td><td>8 L</td><td>1,00</td><td>Focal LVFA</td><td>2</td><td>No delay</td><td>0,8</td><td>Yes</td></tr><tr><td>15</td><td>9 L, 3 R</td><td>0,49</td><td>Focal rythmic spiking</td><td>2</td><td>5</td><td>0,3</td><td>No</td></tr><tr><td>16</td><td>12 R</td><td>0,20</td><td>Focal LVFA</td><td>3</td><td>3</td><td>0</td><td>No</td></tr><tr><td>17</td><td>8 R</td><td>0,47</td><td>Focal rythmic spiking</td><td>2</td><td>No delay</td><td>0,64</td><td>Yes</td></tr></tbody></table>
<figure><img src="image_5.png" /></figure>

Fig. 2 – Example of SEEG data in a patient belonging to nHIP group (patient 10). Part A: Preictal and ictal SEEG data recorded in several brain regions: (I) mesial extra-hippocampal structures (amygdala, entorhinal cortex, mesial temporo-basal region), (II) anterior and posterior hippocampus, and (III) temporal neocortex. Ictal activity began in amygdala at seizure onset (Low voltage fast activity a'2-a'3) and spread secondarily to the hippocampus with a delay of several seconds. Part B: Quantitative analysis of SEEG data obtained through Epileptogenicity index computation. The Epileptogenicity Index (EI) ranks each SEEG bipole according to the tonicity of the discharge and its delay of involvement compared to the seizure onset. The color-coded representation displays the energy ratio between the high frequency (Beta and Gamma band) and the low frequency (Theta and Alpha band) calculated in a sliding window for each bipole during the time course of the seizure. Early involvement of the amygdala and delayed involvement of the hippocampus is clearly evidenced. Part C: MRI slices with SEEG electrode positions. SZ: seizure; HC: hippocampus.

<table><caption>Table 3 – Clinical and paraclinical data in HIP and nHIP groups.</caption><thead><tr><th rowspan="2">Type of surgery</th><th colspan="3">HIP group<br>n = 11</th><th colspan="3">nHIP Group<br>n = 6</th><th rowspan="2">P</th></tr><tr><th>No surgery<br>(n = 5)</th><th>ATL<br>(n = 4)</th><th>TRsH<br>(n = 2)</th><th>ATL<br>(n = 2)</th><th>TRsH<br>(n = 4)</th></tr></thead><tbody><tr><td>Epilepsy onset (years)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean</td><td>19.0</td><td>29.0</td><td>10.0</td><td>5.0</td><td>18.0</td><td>NS</td></tr><tr><td>Median</td><td>19.0</td><td>30.5</td><td>10.0</td><td>5.0</td><td>18.0</td><td></td></tr><tr><td>SD</td><td>7.6</td><td>12.5</td><td>1.4</td><td>1.4</td><td>12.9</td><td></td></tr><tr><td>Language dominant Hemisphere</td><td>5/5</td><td>0/4</td><td>2/2</td><td>1/2</td><td>2/4</td><td>NS</td></tr><tr><td>Frequent focal to bilateral tonic clonic seizures</td><td>0/5</td><td>1/4</td><td>1/2</td><td>0/2</td><td>0/4</td><td>NS</td></tr><tr><td>Delayed Memory deficit</td><td>2/5</td><td>2/4</td><td>0/2</td><td>2/2</td><td>2/4</td><td>NS</td></tr><tr><td>Temporal hypometabolism in FGD-PET</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1</td><td>1</td><td>1</td><td>0</td><td>0</td><td>NS</td></tr><tr><td>Mesial</td><td>4</td><td>0</td><td>1</td><td>0</td><td>2</td><td></td></tr><tr><td>Extra-mesial</td><td>0</td><td>3</td><td>0</td><td>2</td><td>2</td><td></td></tr><tr><td>Hippocampus Interictal activity</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean</td><td>0.71</td><td>0.64</td><td>0.72</td><td>0.84</td><td>0.25</td><td>NS</td></tr><tr><td>Median</td><td>1.0</td><td>0.74</td><td>0.72</td><td>0.84</td><td>0.18</td><td></td></tr><tr><td>SD</td><td>0.40</td><td>0.45</td><td>0.22</td><td>0.22</td><td>0.16</td><td></td></tr><tr><td>Hippocampus</td><td>4/5</td><td>4/4</td><td>2/2</td><td>0/2</td><td>0/4</td><td>P < 0.001</td></tr><tr><td>EI > 0.4</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Seizure elicited by hippocampal stimulation</td><td>4/4</td><td>1/4</td><td>2/2</td><td>NA (0/0)</td><td>0/3</td><td>NS</td></tr></tbody></table>
<table><caption>Table 4 - Surgical outcome in HIP and nHIP groups.</caption><thead><tr><th rowspan="2">Type of surgery</th><th colspan="2">HIP Group<br>(n = 11)</th><th colspan="2">nHIP Group<br>(n = 6)</th><th rowspan="2">P</th></tr><tr><th>ATL<br>(n = 4)</th><th>TRsH<br>(n = 2)</th><th>ATL<br>(n = 2)</th><th>TRsH<br>(n = 4)</th></tr></thead><tbody><tr><td>Surgery outcome</td><td>3</td><td>0</td><td>1</td><td>4</td><td>NS</td></tr><tr><td>Engel class I</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Neuropsychological<br>outcome</td><td>No change (n = 1)</td><td>No change (n = 1)</td><td>Improvement (n = 1)</td><td>No change (n = 2)</td><td></td></tr><tr><td>(when avalaible)</td><td>Worsening (n = 1)</td><td></td><td>Worsening (n = 1)</td><td></td><td></td></tr><tr><td>Histopathological data<br>(when available, 9/12)</td><td>No significant<br>anomalies (n = 1)</td><td>No significant<br>anomalies (n = 1)</td><td>No significant<br>anomalies (n = 1)</td><td>No significant<br>anomalies (n = 3)</td><td>NS</td></tr><tr><td></td><td>Hippocampal<br>sclerosis (n = 1)</td><td>Focal cortical<br>dysplasia (n = 1)</td><td>Focal cortical<br>dysplasia (n = 1)</td><td></td><td></td></tr><tr><td>Follow-up (months)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean</td><td>84.8</td><td>93.0</td><td>61.5</td><td>65.7</td><td>NS</td></tr><tr><td>Median</td><td>61.5</td><td>93.0</td><td>61.5</td><td>64.5</td><td></td></tr><tr><td>SD</td><td>61.0</td><td>63.7</td><td>17.7</td><td>5.9</td><td></td></tr></tbody></table>

ATL: anterior temporal lobectomy; TRsH: Temporal resection sparing the hippocampus; HIP group: hippocampal group; nHIP: non hippocampal group.

I outcome, whereas the two remaining patients had a poor seizure outcome after temporal resection sparing the hippocampus. In the nHIP group all patients (n = 6) underwent surgery. The four patients who underwent temporal resection sparing the hippocampus achieved Engel class I outcome, whereas only one of the two others, who underwent conventional ATL, was seizure free.

Eight patients underwent post-operative neuropsychological evaluation. No change was observed in four patients while improvement was obtained in two. A decrease of verbal memory was observed in the two patients who underwent conventional ATL in the dominant hemisphere.

Histopathological data were available in 9/12 operated patients. It showed no abnormalities in 6 patients, cortical focal dysplasia in 2 and hippocampal sclerosis in 1. None of those lesions were visible on the preoperative MRI. No correlation with EZ organization and surgical outcome was found.

## 4. Discussion

The main findings of this study can be summarized as follows: (1) Surgery should be considered for patients with MRI-normal mTLE, since a significant proportion of patients achieve seizure freedom. (2) Invasive EEG with SEEG provides evidence of different types of seizure organization that cannot be predicted from non-invasive investigations. (3) The choice of surgical procedure should be based on SEEG findings to maximize the chances of surgical success.

Our study emphasizes the importance of SEEG in characterizing the organization of epileptogenic networks in MRI-normal TLE. Within our patient's cohort, who demonstrated with homogeneous semiology indicative of mesial temporal lobe involvement, a higher proportion of seizures was found to originate from the hippocampus. This observation aligns with

a previous SEEG study on patients with TLE having normal MRI, wherein seizure onset exclusively arose from mesial structures in 72% of cases, solely from the lateral temporal cortex in 11% of cases, and from both mesial and neocortical foci in 17% of cases [5]. However, it is important to note that the hippocampus was not the sole trigger of ictal activity. Specifically, we identified two types of seizures associated with non-lesional mTLE: those originating in the hippocampus (65%, 11/17) and those where hippocampal discharge occurred as a secondary event (35%, 6/17). In the latter cases, the discharge originated from either the temporal pole or the amygdala and involved the hippocampus 3 to 10 seconds later. Both visual and quantitative analysis of SEEG signals were consistent in distinguishing between seizures that began in the hippocampus (no delay in visual analysis of ictal hippocampal activity, habitual seizure provoked by hippocampal stimulation, EI > 0.4) and those in which the hippocampal discharge was secondary (delay of at least 1 second in the ictal hippocampal activity, no habitual seizure provoked by hippocampal stimulation, EI < 0.4). However, it is worth noting that interictal SEEG data (normalized spiking activity) did not predict ictal organization.

Importantly, we show also that this ictal organization cannot be predicted by non-invasive workup, including electro-clinical semiology, neuropsychological investigations, or FDG-PET hypometabolism topography, and was only evident through SEEG. Similarly, Lee et al. emphasized the informative role of intracranial EEG evaluations in patients with TLE and negative MRI findings [16].

Regarding surgical outcomes, 70% of the patients underwent surgery, with 67% achieving seizure freedom regardless of the type of surgery performed. The prognosis was similar for patients who underwent surgery with or without hippocampal resection. These results are comparable to epilepsy surgery outcomes in temporal lobe epilepsy with normal MRI findings [17]. Consistent with our study, it has been shown that
sparing or removing an MRI-normal hippocampus yielded similar long-term seizure outcomes [18]. These results suggest that surgery can be considered for patients with mTLE and normal MRI.

However, our study also suggests that surgical treatment should be individualized and based on SEEG data, in order to select the most appropriate surgical technique according to hippocampal involvement. Indeed, SEEG findings lead to the proposal of either an ATL, a TRS H, or a surgical contraindication. We observed favorable outcomes with lobectomy without hippocampal resection only when SEEG showed secondary ictal involvement of the hippocampus. In these cases, all patients became seizure-free (4/4). Conversely, we observed poor outcomes in patients who underwent surgery without hippocampal resection when SEEG indicated initial hippocampal involvement in the seizure (2/2). Thus, we believe that TRS H is possible but only when SEEG data support extra-hippocampal seizure onset, with a time delay greater than 1s for hippocampal involvement.

Our study also shows that it is not justified to contraindicate systematically surgery in mTLE patients with normal MRI because of the risk of post-operative memory decline. Indeed, surgery of mTLE with a preserved hippocampal function is classically associated with postoperative verbal memory deficit in the dominant side and is often contra indicated for most of epilepsy centers [4]. This situation was observed in our two patients who underwent ATL on the dominant hemisphere.

For these patients, surgery may be contraindicated, or a resection that spares mesial structures may be considered, but with a higher risk of failure as compared to classical ATL. Indeed, SEEG can evidence an extra-hippocampal temporal lobe seizure focus that enables a surgery sparing mesial structures that reduces the risk of postsurgical cognitive decline without compromising the chances of seizure freedom. It has been shown that patients with language-dominant TLE had lower rates of postoperative decline in naming and verbal memory when surgery spared the hippocampus [18]. Moreover, the surgical outcome is still favorable when surgical procedure is tailored to SEEG data.

Based on these results, we suggest investigating all patients with drug-resistant mesial TLE and normal MRI for surgical intervention, and not dismissing these patients, especially in cases of dominant TLE and normal memory function, as poor candidates for surgery. In accordance with the proposal of the review of Mulhoffer [3]. Our study emphasizes that SEEG is essential in such situations by demonstrating visually and quantitatively the initial or secondary ictal involvement of the hippocampus, which can not be determined by non invasive presurgical workup. Depending on the SEEG results, several options can be considered: (i) surgery without hippocampal resection (only if SEEG data support extra-hippocampal seizure onset), (ii) surgery with hippocampal resection if the cognitive risk is moderate (in the non-dominant hemisphere or in the presence of preoperative memory deficit), or (iii) surgical contraindication if hippocampal resection is necessary but carries a high risk of memory loss.

One limitation of the study is related to its retrospective design and objectives: our primary objective was to determine

whether the SEEG data allowed us to identify a surgical solution with a moderate cognitive risk in patients who were clinically homogeneous overall. As such, this was not a controlled study allowing systematic evaluation of the efficacy of ATL and TRS H. Nevertheless, we show that the clinical, non-invasive imaging and neuropsychological characteristics of patients who underwent these 2 procedures were broadly comparable in our small cohort. Only SEEG was able to differentiate between them.

In summary, this study establishes that tailored surgical approaches is feasible for individuals with drug-resistant mesial temporal lobe epilepsy (mTLE) and normal MRI findings. This personalized approach demonstrates a substantial probability of attaining seizure freedom, coupled with a carefully assessed risk of cognitive decline. We demonstrate the essential role of Stereo-Electroencephalography (SEEG) in guiding the surgical process through the assessment of hippocampal involvement at the onset of seizures. This aspect plays a pivotal role in deciding whether to consider sparing the hippocampus during discussions about temporal lobectomy while non-invasive investigations lack the requisite accuracy to thoroughly examine this factor.

## Disclosure of interest

Sylvain Rheims received speaker and/or consulting fees from UCB Pharma, Angelini Pharma, EISAI, Livanova, JAZZ Pharma, Medtronic, Zogenix.

Neither of the authors has any conflict of interest to disclose.

## Ethical statement

We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

## Author contributions

HC, JJ and SR designed the study.

HC, KD, MC, AM, SB, JI, WS, PD, JJ, NR, MG, CH and SB collected SEEG data.

MH reviewed all MRI.

VG performed neuropsychological evaluations.

HC, JJ and SR performed visual and quantitative analyses of SEEG data.

JJ performed statistical analyses.

All authors contributed to the preparation of the manuscript.

## Online Supplement. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurol.2024.06.006.
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