# Isolated hippocampal sclerosis and focal dysplasia type IIIa: Comparative study of anatomo-electro-clinical profile and seizure outcome

Mariem Ben Mahmoud, Adrien Benard, Delphine Taussig, Pascale Trebon, Dan Cristian Chiforeanu, Yves Sahler, Arnaud Biraben, Anca Nica, Mihai Dragos Maliia

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Mariem Ben Mahmoud, Adrien Benard, Delphine Taussig, Pascale Trebon, Dan Cristian Chiforeanu, et al.. Isolated hippocampal sclerosis and focal dysplasia type IIIa: Comparative study of anatomo-electro-clinical profile and seizure outcome. Clinical Neurophysiology, 2025, 182, pp.2111461. 10.1016/j.clinph.2025.2111461. hal-05424142

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# Isolated hippocampal sclerosis and focal dysplasia type IIIa: Comparative study of anatomo-electro-clinical profile and seizure outcome

Mariem Ben Mahmoud<sup>a,b</sup>, Adrien Benard<sup>a,c</sup>, Delphine Taussig<sup>d,e</sup>, Pascale Trebon<sup>a</sup>, Dan Cristian Chiforeanu<sup>e</sup>, Yves Sahler<sup>f,g</sup>, Arnaud Biraben<sup>a,c</sup>, Anca Nica<sup>a,c,h</sup>, Mihai Dragos Maliia<sup>a,c,i</sup>

## ARTICLE INFO

### Keywords:

- Temporal lobe epilepsy

- Drug-resistant epilepsy

- Epilepsy surgery

- Hippocampal sclerosis

- Focal cortical dysplasia

- Seizure outcome

## ABSTRACT

**Objective:** Distinguishing drug-resistant temporal lobe epilepsy (TLE) caused by isolated hippocampal sclerosis (iHS) from focal cortical dysplasia type IIIa (FCD IIIa) remains a presurgical challenge. This study aimed to compare the clinical characteristics, electrophysiological data, and postsurgical seizure outcomes between these pathologies.

**Methods:** We retrospectively analyzed a cohort of 50 consecutive TLE patients (mean duration of disease of 22 years) who underwent surgery. The histopathology confirmed either iHS (n = 22) or FCD IIIa (n = 28) and a minimum follow-up of 12 months. The groups were compared on complex presurgical data, surgery type, and outcome.

**Results:** A history of febrile seizures (p = 0.02, OR = 4.7) was more frequent in the FCD IIIa group, which also had significantly lower intelligence quotient (IQ) scores in all domains. The mean total IQ score for FCD IIIa/iHS was 86/94 (p = 0.02); verbal IQ was 85/92 (p = 0.03); performance IQ was 89/98 (p = 0.02). The effect size was considered medium for all three (Cohen's d = 0.7, 0.63 and 0.68 respectively). Scalp EEG showed shorter seizures in FCD IIIa (p = 0.03), in SEEG, the temporal pole was more implanted in this group (p = 0.02, 50 % difference, OR = ∞). At a mean follow-up of 8.5 years, similar seizure-freedom rates was found between groups (82 % for FCD IIIa, 95 % for iHS; p = 0.48). Follow-up EEG and neuropsychological assessment at 6 months post-surgery showed no statistical differences.

**Significance:** FCD IIIa and iHS exhibit several distinct electro-clinical features. The most important is a more impaired general cognitive profile associated with FCD IIIa, without differences in language or global memory.

**Abbreviations:** AMTL, antero-mesial temporal lobectomy; ATL, anterior temporal lobectomy; ASM, anti-seizures medication; DH, dominant hemisphere for language; EEG, electroencephalography; FCD, focal cortical dysplasia; FLAIR, T2-weighted and fluid-attenuated inversion recovery; FS, febrile seizures; HS, hippocampal sclerosis; iHS, isolated hippocampal sclerosis; ILAE, International League against Epilepsy; IQ, intelligence quotient; MRI, magnetic resonance imaging; NDH, non-dominant hemisphere for language; SEEG, stereo-EEG; TLE, temporal lobe epilepsy; V-EEG, video-electroencephalography; WAIS, Wechsler Adult Intelligence Scale; EZ, Epileptic Zone; IZ, Irritative Zone; LZ, Lesional Zone; OR, Odds Ratio; SOZ, Seizure Onset Zone; WMS, Wechsler Memory Scale.

* Corresponding author at: Van Gogh Epileptology Unit, Department of Neurology, CIC 1414, University Hospital (CHU) of Rennes, 2 rue Henri-Le-Guilloux, Rennes Cedex 9, 35033, France.

**E-mail addresses:** Mariem.benmahmoud@fmt.utm.tn (M.B. Mahmoud), Adrien.BENARD@chu-rennes.fr (A. Benard), delphine.taussig@aphp.fr (D. Taussig), pascaletrebon@sfr.fr (P. Trebon), Dancristian.CHIFOREANU@chu-rennes.fr (D.C. Chiforeanu), Yves.SAHLER@chu-rennes.fr (Y. Sahler), arnaud.biraben@universennes1.fr (A. Biraben), Anca.NICA@chu-rennes.fr (A. Nica), Dragos-mihai.maliia@chu-rennes.fr (M.D. Maliia).

<footnote><sup>a</sup> Van Gogh Epileptology Unit, Department of Neurology, CIC 1414, University Hospital (CHU) of Rennes, 2 rue Henri-Le-Guilloux, Rennes Cedex 9, 35033, France</footnote>

<footnote><sup>b</sup> Department of Neurology University Hospital (CHU) Charles Nicolle, Boulevard 9 Avril 1938, Tunis 1006 Tunisia</footnote>

<footnote><sup>c</sup> University of Rennes 1, INSERM, LTSI-U1099, 35000 Rennes, Campus de Beaulieu, Bât 22, 35042 Cedex, Rennes, France</footnote>

<footnote><sup>d</sup> Université Paris Saclay-APHP, Neurophysiology and Epileptology, 78, avenue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France</footnote>

<footnote><sup>e</sup> Department of Anatomic Pathology and Cytopathology, University Hospital (CHU) - Rennes, France 2 rue Henri-Le-Guilloux, Rennes Cedex 9, 35033, France</footnote>

<footnote><sup>f</sup> Department of Neurosurgery, University Hospital (CHU), Rennes, 2 rue Henri-Le-Guilloux, Rennes Cedex 9, 35033, France</footnote>
# 1. Introduction

Surgery for drug-resistant temporal lobe epilepsy (TLE) offers a significant therapeutic option for eligible patients severely affected by their condition. However, the variability in surgical outcomes indicates that multiple complex factors influence the success of this intervention (Pereira Dalio et al., 2022). One key factor frequently cited is the underlying brain lesion, including the presence of hippocampal sclerosis (HS) (Dührsen et al., 2018).

In 2011, Blümcke et al. introduced a revised classification for focal cortical dysplasias (FCD), highlighting the coexistence of HS with extra-hippocampal pathology (Blümcke et al., 2011). It consisted specifically of cortical dyslamination in the temporal neocortex ipsilateral to HS, an entity classified as FCD IIIa (Blümcke et al., 2011; Najm et al., 2022). FCD IIIa is now recognized as a distinct histopathological entity in epilepsy surgery that may impact surgical strategies and postoperative outcomes (Blümcke et al., 2011). No reliable distinction between FCD IIIa and isolated hippocampal sclerosis (iHS) has been established based solely on conventional clinical, electrophysiological, or visual neuro-imaging features during presurgical evaluation (Dührsen et al., 2018). Ambiguity persists, although emerging AI-driven tools show high detection rates for MRI-negative histopathologically-confirmed HS (Ripart et al., 2024).

This study aimed to explore the clinical and electrophysiological features of iHS and FCD IIIa, and to analyze their main differences. For this objective, we considered their history and semiology of their respective associated epilepsies, electrophysiological data, and both short- and long-term postoperative seizure outcomes. The authors considered that this approach could estimate the extent of the epileptic network, guide the presurgical work-up, and, more importantly, support the surgical proposal in TLE patients associated with HS. Additionally, secondly to histopathological diagnosis, these elements could be integrated into a personalized follow-up with tailored risk estimation in terms of recurrence and cognitive sequelae.

# 2. Methods

## 2.1. Patient selection

We performed a retrospective, analytical study. Our cohort consisted of 50 consecutive patients with drug-resistant temporal lobe epilepsy and associated hippocampal sclerosis (HS), chosen from 105 total temporal lobe epilepsy surgeries performed at our center, primarily between 2008 and 2022. They were divided into groups based on histopathological diagnosis aligned to the current ILAE classification (Najm et al., 2022): FCD IIIa (n = 28) and isolated hippocampal sclerosis (iHS, n = 22). To compensate for the well-documented decreasing incidence of iHS in contemporary epilepsy surgery, patients with FCD IIIa were included from 2008, while iHS patients were selected from 1998, maintaining a consistent surgical and evaluation protocol across the entire cohort (Baud et al., 2018).

All patients underwent cortical resections, primarily but not exclusively of the temporal lobe, with a minimum postoperative follow-up of one year. Only cases in which surgical specimens revealed either iHS or FCD IIIa, as per the latest International League Against Epilepsy (ILAE) classification were included (Najm et al., 2022).

## 2.2. Presurgical evaluation

A standardized presurgical evaluation was performed for all participants. This included detailed history and clinical assessments, neuropsychological testing, video-electroencephalography (VEEG) monitoring, and volumetric magnetic resonance imaging (MRI) using 1.5 or 3 T machines per epilepsy protocols.

The neuropsychological assessment, conducted by the same professional for all patients (the author P.T. with 33 years of clinical

experience), included the Wechsler Adult Intelligence Scale (WAIS-III or WAIS-IV) to measure the Full-Scale Intelligence Quotient (IQ), as well as Verbal IQ and Performance IQ. The Wechsler Memory Scale (WMS-R) was used to assess verbal and visual memory. Additionally, the Rapid Battery of Denomination was employed for language screening. To eliminate an ASM medication effect, we calculated the number of different molecules taken by each patient at the moment of the testing. We also did a further analysis on the ASM most prone to provoke cognitive problems, namely Topiramate on language function (Mula et al., 2012), Zonisamide on attention (Akaho, 1996) and Phenobarbital and Benzodiazepines on short and long-term memory and also attention (Malagón-Valdez, 2003; Vining, 1987).

Prolonged VEEG monitoring was performed using scalp electrodes, following a 32-electrode montage based on the modified International 10/10 system. Recording durations ranged from 5 to 10 days with variable treatment withdrawal. The analysis included interictal, ictal and postictal EEG findings. The semiology of recorded seizures was described according to the latest ILAE recommendations (Beniczky et al., 2022; 2025). The clinical data was extracted from the detailed medical records and the seizures recording during VEEG monitoring. All EEG recordings were interpreted by members of the same epileptology team and subsequently reviewed during the multidisciplinary epilepsy surgery concertation. For any missing or ambiguous information, the first author (M.B.M.) reviewed independently the VEEG recordings.

For the ictal recordings a typical seizure start was defined as an initial suppression of background activity, followed by a unilateral rhythmic theta discharge (5-7 Hz) over the anterior or mid-temporal region ipsilateral to the lesion before ictal clinical signs (Pascual, 2007). Atypical patterns may include absence of ictal changes, low-voltage fast activity, rhythmic delta activity, or initial bilateral or contralateral discharges to the epileptogenic lesion (Pascual, 2007).

On preoperative MRI scans, experienced neuroradiologists visually assessed hippocampal alterations. They focused on atrophy, hyperintense signals on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, and the loss of clear anatomical landmarks of the hippocampus in agreement with ILAE's guidelines (Bernasconi et al., 2019). Please note that the analysis was purely based on clinical neuroradiological criteria, without the use of automated detection or quantitative tools. Positron emission tomography and single-photon emission computed tomography data are not reported due to inconsistent availability across all patients.

When non-invasive evaluation was insufficient to precisely delineate the epileptogenic zone, invasive stereo-EEG (SEEG) was employed to accurately define it and assess potential functional limitations. We used SEEG-dedicated depth electrodes, of various lengths depending on the target and the trajectory (Dixi, Beçancon, France). Our center does not utilize other type of cortical electrodes, like grids or strips. This decision was in accordance with the French guidelines of SEEG (Isnard et al., 2018). To further define the epileptogenic network's architecture, the following operational definitions were employed (Bartolomei et al., 2018):

* Lesional Zone (LZ): Contained electrodes recording altered background physiological rhythms, unreactive to adapted physiological stimuli (e.g., disappearance of mu rhythm with motor action) and displaying continuous or predominant slow pathological grapho-elements.

* Irritative Zone (IZ): Included electrodes that displayed spontaneous local pathological sharp or fast activity (e.g., sharp waves, spikes, ripples, and fast ripples).

* Epileptogenic Zone (EZ): Defined as the contacts displaying the seizure onset zone (SOZ), which must precede the clinical onset, as well as the early propagation of the ictal discharge. This was practically defined as the first 5-10 % of the total ictal duration (especially if the pattern was similar to the SOZ, such as low voltage fast activity).
Please note that the analysis was purely based on clinical neuro-
physiological criteria, without the use of automated detection or quan-
titative tools. The hemisphere was divided into 23 unequal cortical
structures based on their importance in the temporal lobe epilepsy
networks (Chassoux et al., 2018) (Supplementary Table 1). Electrode
localization and characterization of the epileptogenic network were
performed using this anatomical framework.

2.3. Surgery

The operability for all the patients was jointly decided in a multi-
disciplinary epilepsy surgery concertation meeting including board-
certified neurologists in epilepsy surgery, neuropsychologists, func-
tional neurosurgeons and neuroradiologists. All patients were operated
in our neurosurgery department, by five different functional neurosur-
geons throughout the years. For each included patient, the postoperative
MRI was verified by our current neurosurgeon, Y.S. He specified if the
temporal lobe resections consisted of a standard or non-standard antero-
mesial temporal lobectomy (AMTL). Non-standard AMTL could be
either extended (resection was extended toward the posterior temporal
structures or extratemporal cortex) or limited (less than the standard
AMTL) (Sheikh et al., 2019).

Succinctly, we defined a standard AMTL in the non-dominant tem-
poral lobe for language as being a resection that consists of the removal
of mesial temporal structures, 5-6 cm at the level of the basal and lateral
temporal cortex and the superior temporal gyrus extending 2-3 cm from
the pole at the level of the central sulcus. Considering the dominant
temporal lobe for language, the extent on the baso-lateral cortex was
limited to 4.5 cm (Spencer & Spencer, 1985). In our center, selective
amygdalo-hippocampectomy was not proposed to TLE patients.

2.4. Histopathological analysis

The surgically resected temporal lobe tissue was immediately fixed
in formalin for preservation. Subsequently, it was meticulously sampled
from predefined regions specified by the neurosurgeon to ensure
comprehensive analysis (hippocampus, amygdala, temporal pole etc.).
These tissue samples underwent routine processing, before being
embedded in paraffin wax. Thin sections were then cut and subjected to
routine hematoxylin and eosin staining for initial morphological eval-
uation. Additionally, a standardized panel of immunohistochemically
markers were performed to further characterize specific cellular ele-
ments and aid in the neuropathological diagnosis as specified by the
recent ILAE guidelines in the diagnostic of FCD (Najm et al., 2022). The
reports between 1998–2004, divided the lesions in either non-Taylor or
Taylor dysplasia (Taylor et al., 1971) and those from 2004 to 2011 in
either type I or type II dysplasia (Palmini et al., 2004). Our current
histopathologist (C.D.C.) then reviewed the original histopathological
reports and slides for all patients in the final cohort to confirm eligibility
and standardize diagnosis according to current nomenclature. The de-
gree of hippocampal sclerosis was graded from minimal (grade I) to
severe (grade V) (Watson et al., 1996).

2.5. Post-operative outcome

Seizure outcome was evaluated according to the Engel classification
system at 1 year and at the latest follow up (Engel, 1993). All patients
underwent postoperative follow-up at 6 months, including a 20-minute
standard EEG, a visual field test and a detailed neuropsychological
reassessment. The same analysis of ASMs taken at the moment of the
revaluation was performed, identical as during the first examination.

2.6. Statistics

Bivariate analyses were used to correlate histopathological diagnosis
with presurgical evaluation and postoperative outcome. Differences

between groups were assessed using two-tailed Fisher's exact or chi-
square tests for categorical variables, and Student's t or Mann-
Whitney tests for continuous variables. Statistical significance was set
at P < 0.05. For the significant differences between the two groups, the
effect size of the comparison was calculated. For continuous variables
the Cohen's d coefficient was employed and the results interpreted as
such (0.2–0.5 small, 0.5–0.8 medium and >0.8 large). For nominal
(categorical) variables, the strength of the association was quantified
using the Odds Ratio (OR). The magnitude was categorized using the
framework developed by Chen et al., (2010), which provides equivalents
to Cohen's d: an OR in the range of 1.68–3.47 indicates a small effect,
3.47–6.71 a medium effect, and an OR ≥ 6.71 a large effect. For negative
associations (OR < 1), the reciprocal (1/OR) is compared to these same
thresholds (values: 0.59, 0.29, and 0.15).

2.7. Data availability

All individual patients' anonymized clinical and paraclinical data are
available in open-access. Access is provided in a Public Repository in a
Microsoft Excel spreadsheet format, adhering to relevant data privacy
regulations. The dataset can be found at https://doi.org/10.6084/m9.
figshare.30264430.

3. Results

3.1. Presurgical clinical assessment

A total of 50 patients with drug-resistant TLE were included in the
study, of whom 28 (56 %) had FCD IIIa and 22 (44 %) had iHS. The sex
distribution was nearly equal (22 males and 28 females). Forty-one
patients were right-handed (82 %), eight were left-handed (16 %), and
one patient was ambidextrous (2 %).

A significantly higher frequency of febrile seizures (FS) was observed
in FCD IIIa patients (n = 17, 60 %; p = 0.024) with a moderate effect size
(OR = 4.12). However, the retrospective design limited the availability
of detailed information regarding FS type (simple or complex). The
mean age at epilepsy onset for the entire group was 14.8 years (range
1–40 years) (p = 0.32). The duration of the disease at surgery was 22.3
years (range 7–52 years) (p = 0.51). Clinical seizure characteristics are
summarized in Table 1.

Seizures frequency did not show any significant difference between
the two groups (p = 0.59). Analyses did not reveal a difference in the
frequency of auras in FCD IIIa patients (24/28, 85 %) compared to iHS
(13/22, 59 %;) although it approached significance (p = 0.051) (Fig. 1).
Epigastric aura was the most common in both FCD IIIa (43 %, n = 12)
and iHS (32 %, n = 7) patients, with no significant group difference (p =
0.98). Manual automatisms were two times more frequent in the iHS
group (60 % vs. 29 %) with a moderate effect size (OR = 0.28).

Loss of awareness was observed in 22 patients with FCD IIIa (79 %) and 19 with iHS (86 %), with no significant difference (p = 0.71). Status epilepticus was reported in only two patients, one in each group. Focal to bilateral tonic-clonic evolution was reported in the history of 28 patients (56 %) (FCD IIIa n = 18 (64 %), iHS n = 10 (45 %), p = 0.14).

3.2. Imaging

MRI findings revealed morphological characteristics consistent with
HS in 43 patients. Of these, 23 were confirmed through histopatholog-
ical examination to have FCD IIIa, and 20 were classified as having iHS
(p = 0.44). Additionally, MRI detected one case of suspected FCD-
related changes in the temporal pole, further confirmed upon neuro-
pathological examination. Due to the historical nature of our cohort, the
visual detection of subtle temporal pole blurring was likely impacted by
variations in MRI field strength and evolving protocols, potentially
leading our neuroradiologists to miss some associated modifications.
<table><caption>**Table 1**
Summary of presurgical clinical characteristics.</caption><thead><tr><th>Clinical and paraclinical variables</th><th></th><th>FCD IIIa (n = 28)</th><th>Isolated HS (n = 22)</th><th>P / Cohens's d or OR</th></tr></thead><tbody><tr><td>Male/female</td><td></td><td>13 (46 %)/15 (54 %)</td><td>9 (40 %)/13 (60 %)</td><td>0.46</td></tr><tr><td>Family history of epilepsy</td><td></td><td>12 (43 %)</td><td>8 (36 %)</td><td>0.42</td></tr><tr><td>History of Febrile Seizure</td><td></td><td>17 (60 %)</td><td>6 (27 %)</td><td>0.024* / 4.12</td></tr><tr><td>Age at seizure onset</td><td></td><td>16.32 ± 12.6</td><td>13.04 ± 10</td><td>0.32</td></tr><tr><td>Duration of epilepsy</td><td></td><td>21.39 ± 11.6</td><td>22 ± 11.83</td><td>0.51</td></tr><tr><td>Age at surgery</td><td></td><td>37.68 ± 11.03</td><td>36.59 ± 9.8</td><td>0.71</td></tr><tr><td>Side of surgery</td><td>Dominant</td><td>14 (50 %)</td><td>13 (60 %)</td><td>0.36</td></tr><tr><td></td><td>Non-dominant</td><td>14 (50 %)</td><td>9 (40 %)</td><td></td></tr><tr><td>HS on MRI</td><td></td><td>23 (82 %)</td><td>20 (90 %)</td><td>0.32</td></tr><tr><td>Seizure frequency</td><td>Daily</td><td>7 (25 %)</td><td>8 (36 %)</td><td>0.59</td></tr><tr><td></td><td>Weekly</td><td>11 (39 %)</td><td>6 (27 %)</td><td></td></tr><tr><td></td><td>Monthly</td><td>10 (36 %)</td><td>8 (36 %)</td><td></td></tr><tr><td>Aura</td><td></td><td>24 (86 %)</td><td>13 (60 %)</td><td>0.051</td></tr><tr><td>Loss of awareness</td><td></td><td>22 (79 %)</td><td>19 (86 %)</td><td>0.71</td></tr><tr><td>Oral automatisms</td><td></td><td>17 (60 %)</td><td>18 (82 %)</td><td>0.13</td></tr><tr><td>Manual automatisms</td><td></td><td>8 (29 %)</td><td>13 (60 %)</td><td>0.044* / 0.28</td></tr><tr><td>Controlateral dystonia</td><td></td><td>6 (21 %)</td><td>5 (23 %)</td><td>0.91</td></tr><tr><td>Autonomic signs</td><td></td><td>11 (39 %)</td><td>11 (50 %)</td><td>0.56</td></tr><tr><td>Aphasia</td><td></td><td>6 (21 %)</td><td>4 (18 %)</td><td>0.53</td></tr><tr><td>Postictal deficit</td><td>Immediate post-seizure recovery</td><td>17 (60 %)</td><td>10 (45 %)</td><td>0.51</td></tr><tr><td></td><td>Confusion</td><td>5 (18 %)</td><td>6 (27 %)</td><td></td></tr><tr><td></td><td>Aphasia</td><td>5 (18 %)</td><td>6 (27 %)</td><td></td></tr><tr><td></td><td>Other deficit</td><td>1 (36 %)</td><td>0</td><td></td></tr><tr><td>Focal to bilateral tonic-clonic evolution</td><td></td><td>18 (64 %)</td><td>10 (45 %)</td><td>0.14</td></tr><tr><td>History of status epilepticus</td><td></td><td>1 (4 %)</td><td>1 (5 %)</td><td>1</td></tr><tr><td>Type of epilepsy</td><td>Standard</td><td>16 (57 %)</td><td>16 (72 %)</td><td>0.31</td></tr><tr><td></td><td>Extended</td><td>9 (33 %)</td><td>3 (14 %)</td><td></td></tr><tr><td></td><td>Limited</td><td>3 (10 %)</td><td>3 (14 %)</td><td></td></tr></tbody></table>

### 3.3. Scalp video-EEG recordings

Intertictal epileptiform abnormalities were comparable between FCD IIIa (24/28, 86 %) and iHS (18/22, 81 %; p = 0.72). These results were consistent regardless of their lateralization (p = 0.63) or their predominant localization on temporal (p = 0.68), or extratemporal electrodes (p = 0.4).

Seizures were recorded on scalp EEG in 49/50 patients during the VEEG assessment. The onset pattern was considered typical in 63 % of FCD IIIa cases and in 45 % of iHS (p = 0.15). Mean ictal EEG duration was significantly longer in iHS patients (2 min 4 sec) than in FCD IIIa (1 min 16 sec; p = 0.034). Comparing ictal and postictal EEG patterns, there were no differences between the groups (Table 2).

### 3.4. SEEG

Nineteen patients (38 %) required an invasive SEEG exploration as part of their presurgical assessment after the multidisciplinary board discussion. Among them, 11 had FCD IIIa (39 %) and eight had iHS (36 %) (p = 0.53). The number of bilateral implantations was identical between the two groups (three patients). The mean number of implanted electrodes per patient was 10.2 (SD ± 2.3), (p = 0.31). The distribution of the number of electrodes and of implanted regions in SEEG, according to histological type is summarized in Supplementary Table 2 and Fig. 2.

Regarding the number of implanted regions (mean 15.4 (SD ± 2.5)) they were similar between groups (p = 0.13). However, the temporal pole was significantly more frequently implanted in FCD IIIa cases compared to iHS (11 vs. 4, p = 0.018) with a large effects size (OR=∞). In analyzing the epileptogenic network notably the seizure onset zone, the inferior insula was involved in (4/9, 50 %) of iSH cases versus (1/10, 9 %) of FCD IIIa cases (p = 0.06). The topography of the lesional and irritative zones was similar between groups (Fig. 2).

### 3.5. Neuropsychological assessment

Epilepsy involved the dominant hemisphere for language in 14 patients with FCD IIIa (50 %) and in 13 patients with iHS (59 %) showing no significant differences between the groups. The assessment of the intelligence quotient (IQ) found significantly lower scores in the overall

Type of aura

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Aura characteristics in the two groups, determined by detailed clinical amanternsis and analysis of recorded seizures during video-EEG monitoring.</figcaption></figure>
<table><caption>**Table 2**
Summary of EEG findings before and 6 months after the surgery.</caption><thead><tr><th colspan="2">EEG findings at presurgical evaluation</th><th>FCD IIIa (n = 28)</th><th>Isolated HS (n = 22)</th><th>p</th></tr></thead><tbody><tr><td rowspan="10">Interictal EEG<br>paroxysmal<br>abnormalities</td><td>Present (n = 42)</td><td>24</td><td>18</td><td>0.71</td></tr><tr><td rowspan="2">Lateralization</td><td>14</td><td>12</td><td>0.63</td></tr><tr><td>Unilateral</td><td>9</td><td>6</td><td></td></tr><tr><td rowspan="5">Unilateral and predominantly on the temporal<br>electrodes</td><td>Bilateral and ipsilateral<br>predominant</td><td>1</td><td>0</td><td></td></tr><tr><td>Bilateral and symmetric</td><td>13</td><td>13</td><td>0.68</td></tr><tr><td>Anterior</td><td>3</td><td>1</td><td></td></tr><tr><td>Basal</td><td>2</td><td>1</td><td></td></tr><tr><td>Posterior</td><td>6</td><td>3</td><td></td></tr><tr><td rowspan="3">Extratemporal electrodes</td><td>Diffuse</td><td>11</td><td>6</td><td>0.4</td></tr><tr><td>Not found</td><td>11</td><td>8</td><td></td></tr><tr><td>Rare</td><td>2</td><td>4</td><td></td></tr><tr><td rowspan="10">Ictal EEG patterns (n = 49)</td><td>Duration</td><td>1 min 16 sec</td><td>2 min 4 sec</td><td>0.034*</td></tr><tr><td rowspan="2">Onset</td><td>17</td><td>9</td><td>0.15</td></tr><tr><td>Atypical</td><td>10</td><td>13</td><td></td></tr><tr><td rowspan="3">Onset distribution</td><td>Anterior temporal region</td><td>11</td><td>11</td><td>0.47</td></tr><tr><td>Basal and posterior-temporal<br>regions</td><td>7</td><td>2</td><td></td></tr><tr><td>Diffuse in the temporal region</td><td>4</td><td>5</td><td></td></tr><tr><td rowspan="5">Core of the ictal discharge</td><td>Extratemporal regions</td><td>5</td><td>4</td><td></td></tr><tr><td>Located mostly in the temporal<br>region</td><td>3</td><td>4</td><td>0.51</td></tr><tr><td>Propagated to the ipsilateral<br>extratemporal regions</td><td>13</td><td>12</td><td></td></tr><tr><td>Propagated to the contralateral<br>temporal lobe</td><td>11</td><td>6</td><td></td></tr><tr><td>Postictal EEG patterns</td><td>Slowing</td><td>Present</td><td>25</td><td>0.11</td></tr><tr><td rowspan="5">Postictal epileptiform abnormalities</td><td rowspan="5">Focal slowing</td><td>Focal temporal</td><td>9</td><td>4</td><td>0.92</td></tr><tr><td>Diffuse<br>temporal</td><td>9</td><td>6</td><td></td></tr><tr><td>Extra temporal</td><td>4</td><td>3</td><td></td></tr><tr><td>Bilateral</td><td>4</td><td>3</td><td></td></tr><tr><td>Postictal epileptiform abnormalities</td><td>6</td><td>6</td><td>0.74</td></tr><tr><td rowspan="2">EEG 6 months after surgery</td><td>Interictal epileptiform abnormalities</td><td>5</td><td>3</td><td>0.49</td></tr><tr><td>Focal slowing</td><td>12</td><td>7</td><td>0.55</td></tr></tbody></table>

FCD IIIa group compared to iHS patients across all domains: total IQ score (mean ± SD: 86 ± 13.55 vs. 94.45 ± 9.73; p = 0.018), in verbal IQ (85.11 ± 12.61 vs. 92.41 ± 10.13, p = 0.033) and performance IQ (89.41 ± 14.82 vs. 98.41 ± 10.65; p = 0.021) (Table 3). These differences were maintained in the non-dominant epilepsies both in the total (p = 0.031) and in the performance domain (p = 0.005). Overall, language and visual memory functions showed no significant group differences. However, in dominant hemisphere epilepsy, verbal memory was significantly more impaired in the FCD IIIa group than iHS (p = 0.015). There was no difference between the groups in terms of the number of ASM at the moment of the evaluation (2.5 ± 0.73 vs. 2.55 ± 0.94 ASM molecules/per patient, p = 0.84). The ratios of patients taking ASM with a strong impact on cognitive functions was also similar (54 % vs. 27 %, p = 0.09) or the number of these type of ASM in patients treated with them.

The presence of a history of FS was not statistically associated with patients' total IQ (p = 0.31), verbal IQ (p = 0.49) and performance IQ (p = 0.3) scores. The evaluation revealed no significant differences in language function (p = 1), verbal memory (p = 0.52) or visual memory (p = 1) functions between patients with and without a history of FS (see Table 3).

### 3.6. Surgical data

The mean age at surgery was 37.2 years (range 12–59 years) and the mean duration of the epilepsy at the time of surgery was 22.3 years (range 7–52 years) (Table 1). Twenty-six patients had left AMTL and 24 right AMTL. Surgery targeted the language-dominant hemisphere in 14 patients with FCD IIIa (50 %) and 13 with iHS (59 %) (p = 0.5). Thirty-

two patients had standard, 12 had extended while six had limited temporal resections. The most common extended AMTL was the inclusion of the ventral anterior insula (apex insulae and portions of limen insulae) proposed in (9/12, 75 % of extended resections) patients. Surgical procedure types were comparable between iHS and FCD IIIa TLE patients. Patients explored by SEEG did not undergo more extended resections (p = 0.17).

### 3.7. Histopathological analysis

The results from the analyzed tissue were divided into 8 anatomical regions for the purpose of this study. The hippocampus was analyzed in all patients (100 %) the amygdala in 96 % and the neocortex in the following order: temporal pole 80 %, superior temporal gyrus 86 %, middle temporal gyrus 100 %, inferior temporal gyrus and temporal base each 35 %, insular cortex 18 % with no difference between the groups. Overall, the FCD IIIa group had a slightly higher number of analyzed structures (6.11 ± 0.93 vs. 5.19 ± 1.16; p < 0.01). A significantly more severe degree of hippocampal sclerosis was observed in the FCD IIIa group (mean grade 4.46 ± 0.99 in 24/28 patients) compared to the iHS group (mean grade 3.00 ± 1.27 in 17/22 patients; p = 0.001). Dyslamination lesions were present across multiple cortical regions in the majority of patients (26/28, 93 %), with a predilection for the anterior and mesial temporal cortex. Insular cortex was analyzed in six patients with FCD IIIa (21 %) and three patients with iHS (14 %). Two of the six FCD IIIa patients (33 %) exhibited signs of dysplasia at this level, characterized by dyslamination, neuronal loss, and heterotopic neurons in the white matter.
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Side by side comparison of implanted (green), lesional (yellow), irritative (violet) and seizure onset zones (red) into isolated hippocampal sclerosis and FCD type IIIa groups in terms of percentage of the entire group.</figcaption></figure>

## 3.8. Postoperative outcome

The average duration of post-surgical follow-up was 8.5 years (range 1–21 years). Short-term (1-year) outcome data revealed that (24/28, 86 %) patients with FCD IIIa and (22/22, 100 %) patients with iHS were in Engel class I (p = 0.12). The average duration between surgery and seizure recurrence was 2 years for FCD IIIa (range 6 months-12 years) and 9 months for iHS (range 6 months-1 year).

At the latest follow-up update, analysis showed that class I outcomes remained roughly stable in the two groups without significant differences (82 % in FCD IIIa and 95 % in iHS) (see Table 4). The large majority of these groups, 21 patients with FCD IIIa (75 %) and 19 patients with iHS (86 %) were completely seizure-free (Engel 1A), (p = 0.48). Engel outcomes based on SEEG data showed no significant group differences. Among the six patients not achieving Engel I outcome, two had undergone SEEG versus four without (p = 1).

All patients underwent a follow-up EEG at 6 months post-surgery, revealing focal slowing in 19 patients (12 had FCD IIIa (43 %), and 7 had iHS (32 %), (p = 0.55)). Epileptiform abnormalities were retrieved in eight of them (5 had FCD IIIa (18 %), and 3 had iHS (14 %) (p = 0.49)) with no association for seizure recurrence (p = 0.33) (Table 2).

The neuropsychological assessment at 6 months post-surgery revealed that 10 patients worsened in the language domain (6 with FCD type IIIa vs. 4 with iHS), 11 patients worsened in the verbal memory domain (7 with FCD IIIa vs. 4 with iHS), and nine patients worsened in the visual memory domain (4 with FCD IIIa vs. 5 with iHS) (Table 3). In language-dominant hemisphere resections, post-surgical worsening of language (p = 0.056) and verbal memory (p = 0.052) approached significance with no relation to histopathological subtype (Table 4). No significant differences were observed in post-surgical visual memory worsening based on histopathological subtype (Table 3) or surgical side (p = 0.44).

## 4. Discussions

In the context of treating drug-resistant TLE, the difficulty in distinguishing between iHS and FCD IIIa at a pre-surgical stage is a pertinent challenge (Jayalakshmi et al., 2022; Mathon et al., 2017; Tezer et al., 2008) identified as such by the ILAE Task Force of histopathology (Najm et al., 2022). Our study compared the pre-surgical electro-clinical profile and the postoperative seizure outcome in patients with iHS and those with FCD type IIIa. The most consistent findings highlight a more impaired general cognitive profile associated with FCD IIIa, including significantly lower IQ scores, alongside a higher prevalence of febrile seizures. Electrophysiological investigation provided evidence of divergent epileptogenic network organization, characterized by significantly shorter ictal EEG duration in FCD IIIa and distinct SEEG findings. Crucially, despite these presurgical differences, our long-term follow-up confirmed excellent and comparable postsurgical seizure-freedom rates for both the FCD IIIa and iHS cohorts.

The analysis of multiple pre-surgical variables has revealed several differences between the two groups. Firstly, we found a significant difference regarding the history of FS, with FS being more common in the FCD IIIa group. These findings are in line with previous studies showing a higher prevalence of FS in patients with FCD IIIa, as reported by (Mühlebner et al., 2016) and (Fauser et al., 2013). This association may reflect a pre-existing structural hippocampal vulnerability, due to genetic factors or early neurodevelopment anomalies (Kasperaviciute et al., 2013; Leal et al., 2017; Tassi et al., 2009). Moreover, an experimental study in methylazoxymethanol acetate-treated rats demonstrated that preexisting cortical dysplasia in the immature brain enhances the epileptogenic effects of prolonged FS, leading to mossy fiber synaptogenesis, neuronal death, and gliosis in the hippocampus (Park et al., 2010). This could explain the earlier seizure onset observed in some FCD IIIa cases, suggesting HS develops from dysplasia-induced
<caption>**Table 3**</caption>

Summary of presurgical neuropsychological assessment and cognitive outcome 6 months after surgical resection in the two groups.

<table><caption>**Table 3 (continued)**</caption><thead><tr><th colspan="2">Neuropsychology tests at presurgical assessment</th><th>FCD IIIa (n = 28)</th><th>Isolated HS (n = 22)</th><th>p/Cohen's d or OR</th></tr></thead><tbody><tr><td rowspan="3">IQ</td><td>Total</td><td>86 ±<br>13.55</td><td>94.45 ±<br>9.73</td><td>0.018* /<br>0.70</td></tr><tr><td>DH</td><td>86.62 ±<br>14.65</td><td>92.77 ±<br>10.28</td><td>0.22</td></tr><tr><td>NDH</td><td>85.43 ±<br>12.98</td><td>96.89 ±<br>8.86</td><td>0.031* /<br>0.99</td></tr><tr><td rowspan="3">Verbal IQ</td><td>Total</td><td>85.11 ±<br>12.61</td><td>92.41 ±<br>10.13</td><td>0.033* /<br>0.63</td></tr><tr><td>DH</td><td>84.46 ±<br>10.95</td><td>92.08 ±<br>10.41</td><td>0.08</td></tr><tr><td>NDH</td><td>85.71 ±<br>14.37</td><td>92.89 ±<br>10.32</td><td>0.21</td></tr><tr><td rowspan="3">Performance IQ</td><td>Total</td><td>89.41 ±<br>14.82</td><td>98.41 ±<br>10.65</td><td>0.021* /<br>0.68</td></tr><tr><td>DH</td><td>90.92 ±<br>17.23</td><td>95.08 ±<br>10.07</td><td>0.47</td></tr><tr><td>NDH</td><td>88 ±<br>12.69</td><td>103.22 ±<br>8.37</td><td>0.005* /<br>1.35</td></tr><tr><td rowspan="3">Pathological Language score</td><td>Total</td><td>4 (14 %)</td><td>3 (14 %)</td><td>0.618</td></tr><tr><td>DH</td><td>3 (21 %)</td><td>3 (23 %)</td><td>0.67</td></tr><tr><td>NDH</td><td>1 (7 %)</td><td>0</td><td>0.61</td></tr><tr><td rowspan="3">Pathological Verbal memory score</td><td>Total</td><td>11 (39 %)</td><td>3 (14 %)</td><td>0.057</td></tr><tr><td>DH</td><td>9 (64 %)</td><td>2 (15 %)</td><td>0.015* /<br>4.74</td></tr><tr><td>NDH</td><td>2 (14 %)</td><td>1 (11 %)</td><td>0.66</td></tr><tr><td rowspan="3">Pathological Visual memory score</td><td>Total</td><td>7 (25 %)</td><td>2 (9 %)</td><td>0.15</td></tr><tr><td>DH</td><td>1 (7 %)</td><td>0</td><td>0.5</td></tr><tr><td>NDH</td><td>6 (42 %)</td><td>2 (22 %)</td><td>0.4</td></tr><tr><td rowspan="3">Treatment</td><td>Number ASM</td><td>2.5 ±<br>0.73</td><td>2.55 ± 0.94</td><td>0.84</td></tr><tr><td>Cognitive ASM</td><td>15 (54 %)</td><td>6 (27 %)</td><td>0.09</td></tr><tr><td>Number Cognitive ASM</td><td>1.2 ±<br>0.54</td><td>1.5 ± 0.5</td><td>0.26</td></tr><tr><td colspan="5" style="text-align: left; font-weight: bold;">Neuropsychology tests 6 months after surgery</td></tr><tr><td rowspan="3">Worsening Language score</td><td>Total</td><td>6 (21 %)</td><td>4 (18 %)</td><td>0.72</td></tr><tr><td>DH</td><td>5 (35 %)</td><td>4 (30 %)</td><td>0.48</td></tr><tr><td>NDH</td><td>1 (7 %)</td><td>0</td><td>0.46</td></tr><tr><td rowspan="3">Worsening Verbal memory score</td><td>Total</td><td>7 (25 %)</td><td>4 (18 %)</td><td>0.63</td></tr><tr><td>DH</td><td>5 (36 %)</td><td>4 (30 %)</td><td>0.48</td></tr><tr><td>NDH</td><td>2 (14 %)</td><td>0</td><td>0.3</td></tr><tr><td rowspan="3">Worsening Visual memory</td><td>Total</td><td>4 (14 %)</td><td>5 (23 %)</td><td>0.58</td></tr><tr><td>DH</td><td>1 (7 %)</td><td>3 (23 %)</td><td>0.44</td></tr><tr><td>NDH</td><td>3 (21 %)</td><td>2 (22 %)</td><td>0.27</td></tr><tr><td rowspan="3">Treatment</td><td>Number ASM</td><td>2.36 ±<br>0.87</td><td>2.05 ± 1.09</td><td>0.21</td></tr><tr><td>Cognitive ASM</td><td>11 (39 %)</td><td>7 (32 %)</td><td>0.76</td></tr><tr><td>Number Cognitive ASM</td><td>1.18 ±<br>0.6</td><td>1.38 ± 0.52</td><td>0.38</td></tr><tr><th colspan="2" style="text-align: left; font-weight: bold;">Neuropsychology tests at presurgical assessment</th><th colspan="2" style="text-align: center;">History of febrile seizures</th><th></th></tr><tr><th colspan="2"></th><th style="text-align: center;">YES</th><th style="text-align: center;">NO</th><th></th></tr><tr><td rowspan="3">IQ</td><td>Total</td><td>91.74 ±<br>13.29</td><td>88.08 ±<br>11.97</td><td>0.31</td></tr><tr><td>DH</td><td>88.62 ±<br>14.30</td><td>89.15 ±<br>11.37</td><td>0.91</td></tr><tr><td>NDH</td><td>95.80 ±<br>11.25</td><td>85.64 ±<br>13.44</td><td>0.07</td></tr><tr><td rowspan="3">Verbal IQ</td><td>Total</td><td>89.65 ±<br>11.65</td><td>87.27 ±<br>12.46</td><td>0.49</td></tr><tr><td>DH</td><td>86.85 ±<br>10.86</td><td>89.54 ±<br>11.90</td><td>0.55</td></tr><tr><td>NDH</td><td>93.30 ±<br>12.19</td><td>84.82 ±<br>14.19</td><td>0.16</td></tr><tr><td>Performance IQ</td><td>Total</td><td>95.61 ±<br>14.90</td><td>91.54 ±<br>12.63</td><td>0.30</td></tr></tbody></table>

<table><thead><tr><th colspan="2">Neuropsychology tests at presurgical assessment</th><th>FCD IIIa (n = 28)</th><th>Isolated HS (n = 22)</th><th>p/Cohen's d or OR</th></tr></thead><tbody><tr><td rowspan="3">Pathological Language score</td><td>DH</td><td>92.15 ±<br>16.70</td><td>90.69 ±<br>10.34</td><td>0.79</td></tr><tr><td>NDH</td><td>100.1 ±<br>11.46</td><td>89.91 ±<br>14.88</td><td>0.094</td></tr><tr><td>Total</td><td>3 (13 %)</td><td>4 (15 %)</td><td>1</td></tr><tr><td rowspan="3">Pathological Verbal memory score</td><td>DH</td><td>2</td><td>4</td><td>0.64</td></tr><tr><td>NDH</td><td>1</td><td>0</td><td>0.47</td></tr><tr><td>Total</td><td>8 (35 %)</td><td>6 (22 %)</td><td>0.52</td></tr><tr><td rowspan="3">Pathological Visual memory score</td><td>DH</td><td>7</td><td>3</td><td>0.22</td></tr><tr><td>NDH</td><td>1</td><td>2</td><td>1</td></tr><tr><td>Total</td><td>4 (17 %)</td><td>5 (19 %)</td><td>1</td></tr><tr><td rowspan="3">Neuropsychology tests at presurgical assessment</td><td>DH</td><td>1</td><td>0</td><td>1</td></tr><tr><td>NDH</td><td>3</td><td>5</td><td>0.65</td></tr></tbody></table>

ASM: anti-seizure medication; IQ: intelligence quotient, DH: dominant hemisphere for language; NDH: non-dominant hemisphere for language.

seizures rather than as a primary lesion (Marusic et al., 2007). However, in our study, epilepsy onset age was not different between groups, highlighting the controversy surrounding the age of seizure onset in these cases (Dührsen et al., 2018).

To further explore potential clinical distinctions between HS and FCD IIIa, we compared seizure semiology. Seizures were shorter and manual automatisms less frequent in FCD IIIa. These findings suggest the existence of different pathophysiological mechanisms that may influence ictal propagation and imply the presence of divergent symptomaticogenic networks associated with dysplasia (Cossu et al., 2021; Ye et al., 2012).

Some authors identified other significant clinical differences when comparing the two groups; for instance, Marusic et al. (2007) reported younger age at surgery and shorter epilepsy duration in FCD IIIa (Marusic et al., 2007). This variability in results could be explained by the diversity of the included populations as well as differences in surgical evaluation across specialized epilepsy surgery centers.

Conversely, similar to findings in our study, the analysis of clinical seizure severity, including the occurrence of focal-to-bilateral tonic-clonic evolution, did not differ by histopathology, suggesting that some clinical features of the network organization do not depend on the lesion type (Kim et al., 2010).

## 4.1. Neuropsychological assessment

The cognitive profile analysis revealed significant impairment in the general intellectual ability of patients with FCD IIIa compared to those with iHS, affecting both performance IQ and verbal IQ. Additionally, verbal memory was statistically more impaired in the dysplasia group. According to Phuong et al., structural brain abnormalities, such as those seen in FCD, can lead to poorer cognitive outcomes (Phuong et al., 2021). The cognitive impairment observed in patients with FCD IIIa can be further explained by the findings of Allone et al., who demonstrated that cortical dysplasia in TLE disrupts essential neural networks involved in multiple domains. Their research indicated that the presence of cortical dysplasia contributes to greater cognitive deficits through disrupted neural connectivity and altered neurodevelopment in the affected brain regions (Allone et al., 2020). Recognizing this distinct cognitive profile in TLE cases may aid in guiding preoperative decisions, as neuropsychological assessment is a key component of the presurgical evaluation and can influence therapeutic strategies. The observed association between FCD IIIa and marked cognitive impairment has been hypothesized to be more strongly linked to the presence of FS (Cheval et al., 2023). These early convulsions might influence cognitive development in this patient population. Our data suggest that cortical malformation are independent predictors of both global and temporal lobe-related cognitive deficits, as a history of febrile seizures was not associated with preoperative cognitive impairment. However, detailed
<table><caption>**Table 4**
Seizure post-surgical outcome at one year and at the last follow-up.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Duration of follow-up</th><th rowspan="2">Engel at I at 1 year</th><th colspan="12">Engel class at the last follow-up</th></tr><tr><th>IA</th><th>IB</th><th>IC</th><th>ID</th><th>IIA</th><th>IIB</th><th>IIC</th><th>IID</th><th>IIIA</th><th>IIIB</th><th>IVA</th><th>IVB</th></tr></thead><tbody><tr><td>FCD IIIa (n = 28)</td><td>8.5 years (range 1–21 years)</td><td>24</td><td>21</td><td>1</td><td>1</td><td>0</td><td>1</td><td>1</td><td>0</td><td>1</td><td>0</td><td>1</td><td>0</td><td>1</td></tr><tr><td>Isolated HS (n = 22)</td><td></td><td>22</td><td>19</td><td>2</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td><td>0</td></tr></tbody></table>

information regarding the frequency and severity of seizures during early childhood was not available for all patients, which limits the strength of this interpretation and should be acknowledged. We acknowledge that cognitive profiles in TLE are likely multifactorial. To address potential confounding, we analyzed variables including history of febrile seizures, epilepsy duration, total number of ASM, and use of ASM with a high propensity for cognitive deficits (See Table 3 for detailed comparison). However, despite excluding these confounding factors, differences in intellectual function remain complex and cannot be solely attributed to the presence of dysplastic cortical tissue in the temporal lobe.

This raises critical questions regarding the precise mechanism of cognitive impairment in FCD IIIa, specifically whether it is a direct consequence of the malformation or is indirectly influenced by underlying focal somatic genetic mutations.

## 4.2. EEG and SEEG

In our study, the analysis of several presurgical variables failed to highlight a distinct EEG profile for patients with FCD IIIa compared to a population with iHS-related TLE. Earlier research that compared EEG features between iHS and FCD IIIa cases did not identify significant distinctions in either interictal or ictal electrical patterns (Cossu et al., 2021). Only Mühlebner et al., reported a tendency towards extended interictal EEG abnormalities and FCD IIIa (Mühlebner et al., 2016).

In our study, the need for intracranial exploration by SEEG did not differ significantly between the two groups, with SEEG being required in 38 % of cases. The temporal pole was more frequently implanted in FCD IIIa cases compared to iHS, aligning with emerging evidence that FCD IIIa often involves the most anterior temporal neocortical regions (Fauser & Schulze-Bonhage, 2006). Furthermore, the trend towards a higher frequency observed for the inferior insula in the SOZ for patients with iHS reflects ongoing discussions about the epileptogenic network organization (Gupta et al., 2020). The insula, a crucial hub in the epileptic network showed significantly higher implication as a seizure onset zone in iHS cases (50 %) compared to FCD IIIa (9 %). This suggests distinct functional network configurations between these conditions without any clear link to the presence of a cortical dyslamination aspect at this level (Mullatti et al., 2019; Xie et al., 2024). However, limited insular neuropathological data hindered full assessment. The increased focus on connectivity models and multimodal imaging has been pivotal in improving the precision of SEEG-based investigations (Bartolomei, 2024; Bartolomei et al., 2017).

## 4.3. Seizure outcome

While anatomo-electro-clinical features remain key predictors of surgical outcome in TLE, etiology may also influence long-term results (Asadi-Pooya et al., 2016). Our findings consistently indicate excellent postoperative outcomes, with long-term stability observed over a follow-up period of 8.5 years. No significant difference was observed between the two groups, either for the early or the late relapse. Less favorable seizure outcome in patients with concomitant HS and FCD has been described previously. They can be attributed to shared developmental or secondary epileptogenic mechanisms, as both may account for a more extensive and severe epileptogenic network (Kim et al., 2010). However, findings remain inconsistent across studies, as Cossu et al.

(2021) found no significant differences in surgical outcomes between patients with iHS and those with dysplasia (Cossu et al., 2021).

Our encouraging results compare or surpass those from anterior temporal lobectomy (ATL) series in iHS (Fauser & Schulze-Bonhage, 2006). This can be possibly explained by a more conservative strategy regarding intracranial exploration, which was performed in 38 % of cases. Additionally, there was a tendency to extend the resection to extratemporal structures (24 % of surgeries), particularly the ventral anterior insula, when semiology suggested or intracranial recorded ictal discharges confirmed synchronous or exhibited rapid propagation at this level. Inclusion of important cortical hubs, such as the piriform cortex (Galovic et al., 2019) and the limen insulae (Chee et al., 2022), both closely linked to mesial temporal networks, was already demonstrated to contribute to favorable outcomes in selected TLE cases.

## 4.4. Limitations

This study has several limitations. As a retrospective study, inherent selection bias is present. The decline in iHS cases in Western countries, mainly due to improved FS management limited our sample size, with an average of one case per year over 22 years. Despite efforts to align results, the evolving official histopathological classification throughout the study period may have introduced bias. This may have underpowered analyses, particularly regarding SEEG profiles and surgical outcomes. Biases in presurgical evaluation also stem from center-specific practices aligned with national guidelines, the evolution of the medical technology during this time frame, and the decision to exclude non-uniformly proposed exams (e.g., nuclear imaging, source imaging). Finally, without a randomized controlled trial, the benefit of extended resections in selected HS cases remains an open question.

## 5. Conclusion

The presurgical identification of neocortical dyslamination associated with HS by MRI remains difficult and somewhat uncertain. Our results have highlighted some significant differences in the electro-clinical profile between patients with FCD IIIa and iHS that could guide the clinician in the pre-surgical diagnostic process, but do not yet allow for a clear and definitive distinction between the two groups. The most consistent results highlight a more impaired general cognitive profile associated with FCD IIIa, without differences in language or global memory performances. Isolating the patients with TLE in the dominant hemisphere, they also exhibited worst verbal memory performance.

Detailed maps of the epileptogenic network organization, derived from the neurophysiological interpretation of rigorous group-level intracranial recordings, are provided. These may serve as a valuable reference for epilepsy surgery centers managing this patient population. To foster a deeper understanding of these seemingly distinct patient groups and their underlying pathophysiology, future research should encompass more comprehensive prospective studies, leveraging modern tools for connectivity and signal analysis.

## Funding statement

None of the authors received funding relevant to this study.
## Ethics approval 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. The patients provided written informed consent for all procedures, analysis, and publication of anonymized clinical data in accordance with the Declaration of Helsinki. All proposed paracological investigations (neuroimaging, non-invasive and invasive EEG recordings) were in accordance with the best standard of care and not modified for research purposes.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

We would like to thank to our colleagues in histopathology Dr. Stéphan Saikali, Dr. Nathalie Le Berre Heresbach and Dr. Sylvie Caulet-Maugendre and neurosurgery Pr. Jean-Marie Scarabin and Dr. Eric Seigneur, Dr. Eduardo Pasqualini, Pr. Claire Haegelen and Dr. Marco Corniola who cared throughout the investigated period for these patients. This study did not receive any funding.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clinph.2025.2111461.

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