Cognitive phenotypes in temporal lobe epilepsy utilizing data- and clinically driven approaches: Moving toward a new taxonomy.

OBJECTIVE: To identify cognitive phenotypes in temporal lobe epilepsy (TLE) and test their reproducibility in a large, multi-site cohort of patients using both data-driven and clinically driven approaches. METHOD: Four-hundred seven patients with TLE who underwent a comprehensive neuropsychological evaluation at one of four epilepsy centers were included. Scores on tests of verbal memory, naming, fluency, executive function, and psychomotor speed were converted into z-scores based on 151 healthy controls (HCs). For the data-driven method, cluster analysis (k-means) was used to determine the optimal number of clusters. For the clinically driven method, impairment was defined as >1.5 standard deviations below the mean of the HC, and patients were classified into groups based on the pattern of impairment. RESULTS: Cluster analysis revealed a three-cluster solution characterized by (a) generalized impairment (29%), (b) language and memory impairment (28%), and (c) no impairment (43%). Based on the clinical criteria, the same broad categories were identified, but with a different distribution: (a) generalized impairment (37%), (b) language and memory impairment (30%), and (c) no impairment (33%). There was a 82.6% concordance rate with good agreement (κ = .716) between the methods. Forty-eight patients classified as having a normal profile based on cluster analysis were classified as having generalized impairment (n = 16) or an isolated language/memory impairment (n = 32) based on the clinical criteria. Patients with generalized impairment had a longer disease duration and patients with no impairment had more years of education. However, patients demonstrating the classic TLE profile (ie, language and memory impairment) were not more likely to have an earlier age at onset or mesial temporal sclerosis. SIGNIFICANCE: We validate previous findings from single-site studies that have identified three unique cognitive phenotypes in TLE and offer a means of translating the patterns into a clinical diagnostic criteria, representing a novel taxonomy of neuropsychological status in TLE.

Interictal coupling of HFOs and slow oscillations predicts the seizure-onset pattern in mesiotemporal lobe epilepsy.

OBJECTIVE: Low-voltage fast activity (LVF) and low-frequency high-amplitude periodic spiking (PS) are the two most common seizure-onset patterns in mesiotemporal lobe epilepsy, with different underlying mechanisms, pathology, and postsurgical outcome. The present work aims to investigate whether specific coupling patterns of high-frequency oscillations (HFOs >80 Hz) and low-frequency waves in the interictal period may distinguish these two patterns, and also seizure-onset zone (SOZ) from non-SOZ as a secondary aim. METHODS: We used intracranial electroencephalography (iEEG) data (during non-rapid eye movement [NREM] sleep) of 18 patients with either LVF or PS seizure-onset patterns. We investigated the interaction between HFOs (ripples: 80-250 Hz and fast ripples: >250 Hz) and slow oscillations (slow-delta, delta, and theta waves). We compared classic features (amplitude, duration, frequency, and power) and phase of coupling between HFOs and slower oscillations inside and outside the SOZ. We then used these features to classify HFOs and subsequently patients into LVF and PS groups. RESULTS: Ripples in the LVF group had significantly longer duration, lower frequency, and higher amplitude than in the PS group. The phase of slow oscillations at which HFOs occur is different between the LVF and PS HFOs (LVF, mostly at the peak or the transition of peak to trough; PS, mostly during the transition of trough to peak). HFOs associated with theta waves best discriminate seizure-onset patterns. The coupling phase improves the classification of HFOs and patients to either LVF or PS groups, and also the classification of HFOs in SOZ and non-SOZ. SIGNIFICANCE: The phase of coupling of HFOs and low-frequency waves may help to not only identify the SOZ, but also to classify patients with different types of seizure-onset patterns. It likely reflects that different disease processes are involved in these patterns during the interictal period.

[Clinical and pathological definition of temporal medium epilepsy subtypes with hypocampic sclerosis]. / Definición clínico-patológica de los subtipos de epilepsia temporal medial con esclerosis del hipocampo.

BACKGROUND AND OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis is the most common cause of refractory epilepsy, and the most common indication for surgery. Although effective, surgery fails in up to 40% of patients. The objective of our study was to establish a correlation between the different histological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis and the prognosis, seizures control, side effects and anticonvulsivant drug withdrawal in patients with refractory epilepsy. PATIENTS AND METHOD: Clinical histories and anatomopathological specimens of 228 patients with temporal epilepsy surgically obtained at our hospital between 1993 and 2014 were retrospectively analysed. All patients underwent a standard preoperative evaluation and anterior temporal resection (modified from Spencer). The anatomopathological study included the standard hematoxylin-eosin and immunohistochemical protocol, with special interest in the assessment of neuronal loss with NeuN. Seizure control was assessed according to the scale of results of the ILAE and Engel. The mean follow-up was 8.6 years (2-19). RESULTS: At 10 years after the intervention, 67.9% of patients were seizure-free (ILAE 1) and as many as 77.5% of the patients were seizure-free (Engel 1) at the end of the follow-up. The probability of not having a seizure (ILAE 1) after surgery at 2 (p=.042), 5 (p=.001) and 7 years (p=.22) was higher in classic and severe forms compared to isolated sclerosis CA1 and CA4 forms. Higher neuronal loss measured with the NeuN immunostain in CA1 was associated with better outcome in seizure management (multivariate analysis, p=.08). The presence of a personal history of epilepsy was associated with greater neuronal loss in CA1 (p=.028) and CA3 (p=.034), and the presence of psychic auras was related with greater neuronal loss in CA3 (p=.025). In our case, the probability of medication withdrawal was related to the presence of personal history (p=.003) and, inversely, to neuronal loss in CA1 (p=.036) and CA3 (p=.038). The greatest impairment of verbal memory occurred in those patients with a lower neuronal loss in CA1 (p=.023), CA2 (p=.049) and CA3 (p=.035). CONCLUSIONS: The results indicate that the classical and severe subtypes have a better prognosis in the control of seizures against the atypical forms, validating the clinical and prognostic utility of the classification of histological subtypes of hippocampal sclerosis from the ILAE. The value of the immunohistochemistry in the mesial temporal lobe epilepsy with hippocampal sclerosis has been demonstrated as a key element to determine the neuropsychological prognosis and seizure management of the patients after surgery.

Characterising subtypes of hippocampal sclerosis and reorganization: correlation with pre and postoperative memory deficit.

Neuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (The 2013 International League Against Epilepsy classification) are based on the qualitative assessment of patterns of neuronal loss with NeuN. In practice, some cases appear indeterminate between type 1 (CA1 and CA4 loss) and type 2 HS (CA1 loss) and we predicted that MAP2 would enable a more stringent classification. HS subtypes, as well as the accompanying alteration of axonal networks, regenerative capacity and neurodegeneration have been previously correlated with outcome and memory deficits and may provide prognostic clinical information. We selected 92 cases: 52 type 1 HS, 15 type 2 HS, 18 indeterminate-HS and 7 no-HS. Quantitative analysis was carried out on NeuN and MAP2 stained sections and a labeling index (LI) calculated for six hippocampal subfields. We also evaluated hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated tau) and mossy-fiber pathway re-organization (ZnT3). Pathology measures were correlated with clinical epilepsy history, memory and naming test scores and postoperative outcomes, at 1 year following surgery. MAP2 LI in indeterminate-HS was statistically similar to type 2 HS but this clustering was not shown with NeuN. Moderate verbal and visual memory deficits were noted in all HS types, including 54% and 69% of type 2 HS. Memory deficits correlated with several pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus (DG) and subiculum and poor preservation of the mossy fiber pathway. Decline in memory at 1 year associated with AT8 labeling in the subiculum and DG but not HS type. We conclude that MAP2 is a helpful addition in the classification of HS in some cases. Classification of HS subtype, however, did not significantly correlate with outcome or pre- or postoperative memory dysfunction, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.

Usefulness of StereoEEG-based tailored surgery for medial temporal lobe epilepsy. Preliminary results in 11 patients.

OBJECTIVE: Surgical options for medial temporal lobe epilepsy (MTLE) include anterior temporal lobectomy (ATL) and selective amygdalohippocampectomy (SAH). Optimal criteria for choosing the appropriate surgical approach remain uncertain. This article reports 11 consecutive cases in which electrophysiological findings of stereoelectroencephalography (SEEG) were used to determine the optimal surgical approach. PATIENTS AND METHODS: Eleven consecutive patients with MTLE underwent SEEG evaluation and were placed in either the medial or the medial+lateral group based on the findings. Patients in the medial group underwent SAH using the subtemporal approach, and patients in the medial+lateral group underwent SEEG-guided anterior temporal lobectomy. SEEG findings were also compared with other examinations including flumazenil (FMZ)-positron emission tomography (PET), fluorine-18 labeled fluorodeoxyglucose (FDG)-PET, and magnetoencephalography (MEG). Results were evaluated to determine which examinations most consistently identified the epileptogenic zone. RESULTS: Of the 11 cases, 4 patients were placed in the medial group, and 7 patients in the medial+lateral group. Of patients, 90.9% were classified in class I of the Engel Epilepsy Surgery Outcome Scale, while 72.7% were classified in class I by the International League Against Epilepsy (ILAE) system. Analyzed by group, 100% of the medial group experienced an Engel class I outcome in the medial group, compared to 85.7% in the medial+lateral group. SEEG findings were comparable with FDG-PET results (10 of 11, 91%). CONCLUSION: Tailored surgery guided by SEEG is an electrophysiologically feasible treatment for MTLE that can result in favorable outcomes. Although seizures are thought to originate in the medial temporal lobe in MTLE, it is important for involvement of the lateral temporal cortex to be also considered in some cases.

Magnetic resonance imaging connectivity for the prediction of seizure outcome in temporal lobe epilepsy.

OBJECTIVE: Currently, approximately 60-70% of patients with unilateral temporal lobe epilepsy (TLE) remain seizure-free 3 years after surgery. The goal of this work was to develop a presurgical connectivity-based biomarker to identify those patients who will have an unfavorable seizure outcome 1-year postsurgery. METHODS: Resting-state functional and diffusion-weighted 3T magnetic resonance imaging (MRI) was acquired from 22 unilateral (15 right, 7 left) patients with TLE and 35 healthy controls. A seizure propagation network was identified including ipsilateral (to seizure focus) and contralateral hippocampus, thalamus, and insula, with bilateral midcingulate and precuneus. Between each pair of regions, functional connectivity based on correlations of low frequency functional MRI signals, and structural connectivity based on streamline density of diffusion MRI data were computed and transformed to metrics related to healthy controls of the same age. RESULTS: A consistent connectivity pattern representing the network expected in patients with seizure-free outcome was identified using eight patients who were seizure-free at 1-year postsurgery. The hypothesis that increased similarity to the model would be associated with better seizure outcome was tested in 14 other patients (Engel class IA, seizure-free: n = 5; Engel class IB-II, favorable: n = 4; Engel class III-IV, unfavorable: n = 5) using two similarity metrics: Pearson correlation and Euclidean distance. The seizure-free connectivity model successfully separated all the patients with unfavorable outcome from the seizure-free and favorable outcome patients (p = 0.0005, two-tailed Fisher's exact test) through the combination of the two similarity metrics with 100% accuracy. No other clinical and demographic predictors were successful in this regard. SIGNIFICANCE: This work introduces a methodologic framework to assess individual patients, and demonstrates the ability to use network connectivity as a potential clinical tool for epilepsy surgery outcome prediction after more comprehensive validation.

Is 'burned-out hippocampus' syndrome a distinct electro-clinical variant of MTLE-HS syndrome?

AIM: To study the clinical, electrophysiological and imaging characteristics of patients with unilateral mesial temporal lobe epilepsy (MTLE) with contralateral ictal onset on scalp EEG, viz. 'burned-out hippocampus' syndrome (MTLE-BHS). METHODS: MTLE-BHS was defined as TLE with unilateral hippocampal sclerosis (HS) without any dual pathology on MRI and contralateral ictal onset on scalp EEG, unlike in classical hippocampal sclerosis (HS). Consecutive "MTLE-BHS" patients evaluated at our Centre for Comprehensive Epilepsy Care from January 2005 to July 2014 were studied. Twenty-five cases of classic MTLE-HS operated during the same period were also analyzed for comparison. RESULTS: Seventeen patients were diagnosed to have MTLE-BHS. Mean age of seizure onset was 9.5±7.7years and the mean duration of epilepsy was18.2±7.3years. Epigastric aura was more common in MTLE-HS and fear, secondary generalized seizures and temporal polar changes on MRI were more prevalent in the MTLE-BHS subgroup. In the latter group, five (29%) exhibited seizure semiology and 2 (12%) had interictal discharges discordant to the side of MTS. Eight (47%) patients in the MTLE-BHS sub-group had normal medial temporal volume on Scheltens scale. Eight patients among MTLE-BHS underwent surgery (4 following intracranial monitoring that localized to the side of HS) with Engel class I outcome at 1year follow-up in 6 and Engel class II outcome in 2. CONCLUSION: Attenuation of ipsilateral fast ictal rhythms on scalp EEG as well as neocortical changes are likely to be deterministic factors for MTLE-BHS as opposed to the severity of hippocampal atrophy. Considering good post-operative outcomes, intracranial monitoring for surgical selection is not mandatory in MTLE-BHS despite discordant semiology and ictal onset, in the presence of inter-ictal, functional imaging and neuropsychology data concordant to the side of HS.

Electrophysiological resting-state biomarker for diagnosing mesial temporal lobe epilepsy with hippocampal sclerosis.

The main aim of the present study was to evaluate whether resting-state functional connectivity of magnetoencephalography (MEG) signals can differentiate patients with mesial temporal lobe epilepsy (MTLE) from healthy controls (HC) and can differentiate between right and left MTLE as a diagnostic biomarker. To this end, a support vector machine (SVM) method among various machine learning algorithms was employed. We compared resting-state functional networks between 46 MTLE (right MTLE=23; left MTLE=23) patients with histologically proven HS who were free of seizure after surgery, and 46 HC. The optimal SVM group classifier distinguished MTLE patients with a mean accuracy of 95.1% (sensitivity=95.8%; specificity=94.3%). Increased connectivity including the right posterior cingulate gyrus and decreased connectivity including at least one sensory-related resting-state network were key features reflecting the differences between MTLE patients and HC. The optimal SVM model distinguished between right and left MTLE patients with a mean accuracy of 76.2% (sensitivity=76.0%; specificity=76.5%). We showed the potential of electrophysiological resting-state functional connectivity, which reflects brain network reorganization in MTLE patients, as a possible diagnostic biomarker to differentiate MTLE patients from HC and differentiate between right and left MTLE patients.

The new approach to classification of focal epilepsies: Epileptic discharge and disconnectivity in relation to cognition.

The new classification of epilepsy stratifies the disease into an acute level, based on seizures, and an overarching chronic level of epileptic syndromes (Berg et al., 2010). In this new approach, seizures are considered either to originate and evolve in unilateral networks or to rapidly encompass both hemispheres. This concept extends the former vision of focal and generalized epilepsies to a genuine pathology of underlying networks. These key aspects of the new classification can be linked to the concept of cognitive curtailing in focal epilepsy. The present review will discuss the conceptual implications for acute and chronic cognitive deficits with special emphasis on transient and structural disconnectivity. Acute transient disruption of brain function is the hallmark of focal seizures. Beyond seizures, however, interictal epileptic discharges (IEDs) are increasingly recognized to interfere with physiological brain circuitry. Both concomitant EEG and high-precision neuropsychological testing are necessary to detect these subtle effects, which may concern task-specific or default-mode networks. More recent data suggest that longstanding IEDs may affect brain maturation and eventually be considered as a biomarker of pathological wiring. This brings us to the overarching level of chronic cognitive and behavioral comorbidity. We will discuss alterations in structural connectivity measured with diffusion-weighted imaging and tractography. Among focal epilepsies, much of our current insights are derived from temporal lobe epilepsy and its impact on neuropsychological and psychiatric functioning. Structural disconnectivity is maximal in the temporal lobe but also concerns widespread language circuitry. Eventually, pathological wiring may contribute to the clinical picture of cognitive dysfunction. We conclude with the extrapolation of these concepts to current research topics and to the necessity of establishing individual patient profiles of network pathology with EEG, high-precision neuropsychological testing, and state-of-the-art neuroimaging. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy".

Clinical and electrophysiological findings in mesial temporal lobe epilepsy with hippocampal sclerosis, based on the recent histopathological classifications.

BACKGROUND: Hippocampal sclerosis (HS) is a common pathology in MTLE, patients may show different surgical outcomes and clinical features. The 2013 ILAE classification subdivides HS into 3 types (HS type 1: severe neuronal loss and gliosis predominantly in CA1 and CA4 regions; - HS type 2: CA1 predominant; HS type 3: CA4 predominant) and includes "gliosis only, as no-HS". The association of clinical and electrophysiological findings with different HS types has not been reported previously in detail. METHODS: 48 patients who had undergone temporal lobectomy with amygdalohippocampectomy due to mesial TLE-HS between February 2014 and February 2016 were included. The patients were divided into five groups: patients with HS ILAE type 1, HS ILAE type 2, HS ILAE type 3, FCD type IIIa, or gliosis/no HS. The correlation between HS ILAE types and clinical/EEG findings in patients with MTLE due to HS was investigated. RESULTS: Of the 48 patients 30 were male. In 23 patients, the resection was on the left side (48%). Three patients had only gliosis, 25 patients had HS ILAE type 1, 7 had HS ILAE type 2, and 4 had HS ILAE type 3. Nine of the 48 patients had cortical lamination abnormalities in the temporal lobe associated with HS (FCD type IIIa). All patients were seizure free for early follow up. There was no association between type of HS in terms of duration of epilepsy, onset age of epilepsy, lateralized or localized semiological findings, or interictal/ictal EEG findings. Family history of epilepsy or SGTCSs were statistically more frequent in patients with types 2 and 3 HS and status epilepticus was more frequent in patients with HS-FCD type IIIa. CONCLUSION: The patients with HS types 2 and 3 have more frequent SGTCS or status epilepticus as well as increased family history of epilepsy. These findings can be helpful in understanding the epileptogenicity-prognoses of HS.

Resting-state functional MRI distinguishes temporal lobe epilepsy subtypes.

OBJECTIVE: We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS). METHODS: Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level-dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions. RESULTS: The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness. SIGNIFICANCE: This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.

Rethinking cognition and behavior in the new classification for childhood epilepsy: Examples from frontal lobe and temporal lobe epilepsies.

The new approach to classification of the epilepsies emphasizes the role of dysfunction in networks in defining types of epilepsies. This paper reviews the structural and neuropsychological deficits in two types of childhood epilepsy: frontal lobe and temporal lobe epilepsy. The evidence for and against a pattern of specificity of deficits in executive function and memory associated with these two types of epilepsies is presented. The evidence varies with the methodologies used in the studies, but direct comparison of the two types of epilepsies does not suggest a clear-cut mapping of function onto structure. These findings are discussed in light of the concept of network dysfunction. The evidence supports the conceptualization of epilepsy as a network disease. Implications for future work in the neuropsychology of pediatric epilepsy are suggested. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy".

Pathology-Based Approach to Seizure Outcome After Surgery for Pharmacoresistant Medial Temporal Lobe Epilepsy.

BACKGROUND: Hippocampal sclerosis (HS) is the most common cause of drug-resistant medial temporal lobe epilepsy (MTLE). Structural abnormalities such as HS, granule cell pathology (GCP), and focal cortical dysplasia (FCD) have been classified histopathologically, possibly allowing a more accurate assessment of prognostic seizure and neuropsychologic outcomes. We correlated seizure outcome with comprehensive temporal lobe pathologic findings, identified according to the most recent classification systems of HS, GCP, and FCD. METHODS: All the 83 patients who underwent anterior temporal lobectomy (ATL) for drug-resistant MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were collected. Patients were divided in 2 main groups: 1) isolated HS with/without GCP (HS +/- GCP); and 2) HS associated with FCD with/without GCP (HS+FCD +/- GCP). Patients were followed up at least 1 year, and seizure outcome was reported in accordance with Engel classification. RESULTS: Group I: HS +/- GCP: Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-no GCP (P < 0.05). Moreover, a better outcome for the patients affected by GCP type I was observed (P < 0.05). Group II: HS+FCD +/- GCP: Patients with HS variant type I presented a better seizure outcome than the patients with HS type II (Engel class IA HS type I vs. type II: 69% vs. 40%). CONCLUSIONS: A pathology-based approach to epilepsy surgery might improve the interpretation of the results, could predict which cases will enjoy a better seizure outcome, and could help to the comprehension of the causes of failures.

Clinico-pathological subtypes of hippocampal sclerosis in temporal lobe epilepsy and their differential impact on memory impairment.

Hippocampal anatomy and network organization are capable to generate drug-resistant temporal lobe epilepsy (TLE) in humans and particularly vulnerable to segmental neuronal cell loss. Surgical hippocampectomy has been proven successful in treatment and available human tissue specimens allow systematic clinico-pathological examination. Different patterns of hippocampal cell loss have been identified in TLE patients and are recently classified by the International League against Epilepsy (ILAE) into four distinct subtypes in order to stratify the heterogenous group of TLE patients also with respect to postsurgical outcome. Another important aim of the international consensus classification system of hippocampal sclerosis (HS) is to gain further insights into the morpho-functional organization of human memory frequently compromised in TLE patients.

Ictal depth EEG and MRI structural evidence for two different epileptogenic networks in mesial temporal lobe epilepsy.

Hypersynchronous (HYP) and low voltage fast (LVF) activity are two separate ictal depth EEG onsets patterns often recorded in presurgical patients with MTLE. Evidence suggests the mechanisms generating HYP and LVF onset seizures are distinct, including differential involvement of hippocampal and extra-hippocampal sites. Yet the extent of extra-hippocampal structural alterations, which could support these two common seizures, is not known. In the current study, preoperative MRI from 24 patients with HYP or LVF onset seizures were analyzed to determine changes in cortical thickness and relate structural changes to spatiotemporal properties of the ictal EEG. Overall, onset and initial ipsilateral spread of HYP onset seizures involved mesial temporal structures, whereas LVF onset seizures involved mesial and lateral temporal as well as orbitofrontal cortex. MRI analysis found reduced cortical thickness correlated with longer duration of epilepsy. However, in patients with HYP onsets, the most affected areas were on the medial surface of each hemisphere, including parahippocampal regions and cingulate gyrus, whereas in patients with LVF onsets, the lateral surface of the anterior temporal lobe and orbitofrontal cortex showed the greatest effect. Most patients with HYP onset seizures were seizure-free after resective surgery, while a higher proportion of patients with LVF onset seizures had only worthwhile improvement. Our findings confirm the view that recurrent seizures cause progressive changes in cortical thickness, and provide information concerning the structural basis of two different epileptogenic networks responsible for MTLE. One, identified by HYP ictal onsets, chiefly involves hippocampus and is associated with excellent outcome after standardized anteromedial temporal resection, while the other also involves lateral temporal and orbitofrontal cortex and a seizure-free surgical outcome occurs less after this procedure. These results suggest that a more extensive tailored resection may be required for patients with the second type of MTLE.

Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification.

OBJECTIVE: Focal cortical dysplasias (FCDs) represent a common architectural cortical disorder underlying pharmacoresistant focal epilepsy. The recent ILAE classification defines different types of FCDs based on their histopathological features, MRI imaging, and presumed pathogenesis; however, their clinical features and their prognostic significance are still incompletely defined. In addition, the combination of different histopathological abnormalities can represent "unusual" subtypes that can be difficult to classify. The aim of our study was to analyze the incidence and the significance of these "unusual" subtypes of FCDs in drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: We retrospectively analyzed 133 patients consecutively submitted to tailored anteromesial temporal lobe resection for pharmacoresistant MTLE. Seizure onset, seizure duration, age at surgery, and postoperative seizure outcome were evaluated in relation to the different neuropathological groups defined according to the new ILAE classification. RESULTS: Focal cortical dysplasias were found in 80 out of 133 patients. Six patients were affected by isolated FCD type I, 12 patients by FCD type II, and 44 patients by FCD type III. Furthermore, we found 18 "atypical" cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of associated FCD type II-hippocampal sclerosis (HS) and 8 cases associated with FCD II-epilepsy-associated tumors (EATs). CONCLUSION: Our results indicate that "unusual" subtypes of FCDs, in particular associated FCD type II, are not uncommon findings, suggesting that they deserve a classification recognition. Similarities in seizure outcome and immunohistochemical and molecular evidences, shared by FCD type II+EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to also include "associated FCD type II" in the definition of the new unifying class FCD type III should be further discussed.

18FDG-PET in different subtypes of temporal lobe epilepsy: SEEG validation and predictive value.

OBJECTIVE: The objective of the study was to characterize interictal 18-fluorodeoxyglucose-positron emission tomography ((18) FDG-PET) whole-brain voxel-based metabolic patterns among distinct subtypes of temporal lobe epilepsy (TLE), as defined by stereo-electroencephalography (SEEG) and to determine predictive value of PET result on postoperative outcome. METHODS: Fifty-four consecutive patients with pharmacoresistant TLE were enrolled retrospectively after a comprehensive presurgical evaluation. This evaluation defined: 7 lateral TLE, 17 mesial TLE, 14 "plus" TLE, and 16 bilateral TLE. Whole-brain voxel-based brain metabolism was studied in each group of patients, in comparison to 23 healthy subjects, and individual classification was evaluated by cross-validation using the found clusters. An (18) FDG-PET index was moreover calculated for each patient, based on the individual Z-score of the most significant cluster extracted on the comparison between patients' subgroup and healthy subjects. Logistic regression analysis was used to estimate factors associated with postoperative outcome (Engel's classes III-IV vs. I-II), including age, gender, disease duration, seizure frequency, as well as magnetic resonance imaging (MRI) and PET findings. RESULTS: Different patterns of hypometabolism were found inside and outside the epileptogenic zone, among patients with distinct subgroups of TLE, in comparison to healthy subjects (p < 0.001, corrected for the cluster). At individual level, cross-validation showed satisfactory discrimination between the four groups with 71.4-88.2% overall accuracy. Multivariate analysis shows that (18) FDG-PET index was the only significant predictor of postoperative outcome to distinguish between Engel's classes I-II and III-IV (p = 0.037). SIGNIFICANCE: Overall, this whole-brain voxel-based analysis validates specific patterns of hypometabolism, inside and outside the EZ, in distinct subgroups of patients with TLE, as defined by SEEG gold standard, and in relation with postoperative outcome.

Magnetic resonance imaging pattern learning in temporal lobe epilepsy: classification and prognostics.

OBJECTIVE: In temporal lobe epilepsy (TLE), although hippocampal atrophy lateralizes the focus, the value of magnetic resonance imaging (MRI) to predict postsurgical outcome is rather modest. Prediction solely based on the hippocampus may be hampered by widespread mesiotemporal structural damage shown by advanced imaging. Increasingly complex and high-dimensional representation of MRI metrics motivates a shift to machine learning to establish objective, data-driven criteria for pathogenic processes and prognosis. METHODS: We applied clustering to 114 consecutive unilateral TLE patients using 1.5T MRI profiles derived from surface morphology of hippocampus, amygdala, and entorhinal cortex. To evaluate the diagnostic validity of the classification, we assessed its yield to predict outcome in 79 surgically treated patients. Reproducibility of outcome prediction was assessed in an independent cohort of 27 patients evaluated on 3.0T MRI. RESULTS: Four similarly sized classes partitioned our cohort; in all, alterations spanned over the 3 mesiotemporal structures. Compared to 46 controls, TLE-I showed marked bilateral atrophy; in TLE-II atrophy was ipsilateral; TLE-III showed mild bilateral atrophy; whereas TLE-IV showed hypertrophy. Classes differed with regard to histopathology and freedom from seizures. Classwise surface-based classifiers accurately predicted outcome in 92 ± 1% of patients, outperforming conventional volumetry. Predictors of relapse were distributed bilaterally across structures. Prediction accuracy was similarly high in the independent cohort (96%), supporting generalizability. INTERPRETATION: We provide a novel description of individual variability across the TLE spectrum. Class membership was associated with distinct patterns of damage and outcome predictors that did not spatially overlap, emphasizing the ability of machine learning to disentangle the differential contribution of morphology to patient phenotypes, ultimately refining the prognosis of epilepsy surgery.

Mesial temporal lobe epilepsy: a distinct electroclinical subtype of temporal lobe epilepsy.

Mesial temporal lobe epilepsy is a common subtype of temporal lobe epilepsy. Its most common cause is hippocampal sclerosis, which contributes to its distinct electroclinical phenotype that is seen commonly in the epilepsy monitoring unit setting. The common electrophysiological data show anterior temporal interictal sharp waves as well as rhythmic theta activity in the same localization. While the electrophysiological data can at times be misleading, its stereotyped and characteristic semiology can often allow for accurate diagnosis on its own. As patients with mesial temporal lobe epilepsy often fail medical therapy, surgical therapy can be considered. Early accurate diagnosis in these patients is essential for optimal care.