Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated ß-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

EANM practice guidelines for an appropriate use of PET and SPECT for patients with epilepsy.

Epilepsy is one of the most frequent neurological conditions with an estimated prevalence of more than 50 million people worldwide and an annual incidence of two million. Although pharmacotherapy with anti-seizure medication (ASM) is the treatment of choice, ~30% of patients with epilepsy do not respond to ASM and become drug resistant. Focal epilepsy is the most frequent form of epilepsy. In patients with drug-resistant focal epilepsy, epilepsy surgery is a treatment option depending on the localisation of the seizure focus for seizure relief or seizure freedom with consecutive improvement in quality of life. Beside examinations such as scalp video/electroencephalography (EEG) telemetry, structural, and functional magnetic resonance imaging (MRI), which are primary standard tools for the diagnostic work-up and therapy management of epilepsy patients, molecular neuroimaging using different radiopharmaceuticals with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) influences and impacts on therapy decisions. To date, there are no literature-based praxis recommendations for the use of Nuclear Medicine (NM) imaging procedures in epilepsy. The aims of these guidelines are to assist in understanding the role and challenges of radiotracer imaging for epilepsy; to provide practical information for performing different molecular imaging procedures for epilepsy; and to provide an algorithm for selecting the most appropriate imaging procedures in specific clinical situations based on current literature. These guidelines are written and authorized by the European Association of Nuclear Medicine (EANM) to promote optimal epilepsy imaging, especially in the presurgical setting in children, adolescents, and adults with focal epilepsy. They will assist NM healthcare professionals and also specialists such as Neurologists, Neurophysiologists, Neurosurgeons, Psychiatrists, Psychologists, and others involved in epilepsy management in the detection and interpretation of epileptic seizure onset zone (SOZ) for further treatment decision. The information provided should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals and imaging modalities.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Towards a better identification of ictal semiology patterns in insular epilepsies: A stereo-EEG study.

OBJECTIVE: To describe pure insular ictal semiology and patterns of extra-insular spread demonstrated by stereoelectroencephalography (SEEG) according to a classification based on the insular cytoarchitecture. METHODS: We investigated the ictal semiology in 17 patients undergoing SEEG for insular epilepsy. The insular cortex was divided into three regions roughly overlapping with the agranular, dysgranular and granular regions. Ictal semiology was described accordingly: anterior insula (AI, short anterior and middle gyri), middle insula (MI, short posterior and long anterior gyri) and posterior insula (PI, long posterior gyrus). RESULTS: Awareness impairment occurred secondarily to extra-insular ictal spread. Subjective manifestations were constant. AI seizures (n = 3) presented with autonomic (increased heart rate [HR], respiratory changes), oropharyngeal (mainly throat sensations), emotional (fear, anguish) semiology and the "hand-to-throat" sign followed by frontal-like semiology. MI seizures (n = 8) presented with mainly non-painful paresthesia, some autonomic (respiratory, increased HR), oropharyngeal or thermic symptoms and early motor features with spread to the opercular cortex. PI seizures (n = 6) were characterized by somatosensory semiology, mainly paresthesia potentially painful, and cephalic sensations. CONCLUSIONS: Cytoarchitectonic-based classification and the corresponding ictal features support the antero-posterior grading of insular seizures and highlight specific ictal symptoms. SIGNIFICANCE: This refinement of insular semiology can help optimize the planning of SEEG for presumed insular epilepsy.

Transuncal Selective Amygdalohippocampectomy by an Inferolateral Preseptal Endoscopic Approach Through Inferior Eyelid Conjunctival Incision: An Anatomic Study.

BACKGROUND: Transorbital endoscopic approaches have been described for pathologies of anterior and middle fossae. Standard lateral orbitotomy gives access to mesial temporal lobe, but the axis of work is partially obscured by the temporal pole and working corridor is limited. OBJECTIVE: To evaluate the usefulness of an inferolateral orbitotomy to provide a more direct corridor to perform a transuncal selective amygdalohippocampectomy. METHODS: Three adult cadaveric specimens were used for a total of 6 dissections. A step-by-step description and illustration of the transuncal corridor for a selective amygdalohippocampectomy were performed using the inferolateral orbitotomy through an inferior eyelid conjunctival incision. The anatomic landmarks were demonstrated in detail. Orbitotomies and angles of work were measured from computed tomography scans, and the area of resection was illustrated by postdissection MRI. RESULTS: Inferior eyelid conjunctival incision was made for exposure of the inferior orbital rim. Inferolateral transorbital approach was performed to access the transuncal corridor. Endoscopic selective amygdalohippocampectomy was performed through the entorhinal cortex without damage to the temporal neocortex or Meyer's loop. The mean horizontal diameter of the osteotomy was 14.4 mm, and the vertical one was 13.6 mm. The mean angles of work were 65° and 35.5° in the axial and sagittal planes, respectively. Complete amygdalohippocampectomy was achieved in all 6 dissections. CONCLUSION: Transuncal selective amygdalohippocampectomy was feasible in cadaveric specimens using the inferolateral transorbital endoscopic approach avoiding damage to the temporal neocortex and Meyer's loop. The inferior eyelid conjunctival incision may result in an excellent cosmetic outcome.

Predictors of outcomes after surgery for medically intractable insular epilepsy: A systematic review and individual participant data meta-analysis.

Insular epilepsy (IE) is an increasingly recognized cause of drug-resistant epilepsy amenable to surgery. However, concerns of suboptimal seizure control and permanent neurological morbidity hamper widespread adoption of surgery for IE. We performed a systematic review and individual participant data meta-analysis to determine the efficacy and safety profile of surgery for IE and identify predictors of outcomes. Of 2483 unique citations, 24 retrospective studies reporting on 312 participants were eligible for inclusion. The median follow-up duration was 2.58 years (range, 0-17 years), and 206 (66.7%) patients were seizure-free at last follow-up. Younger age at surgery (≤18 years; HR = 1.70, 95% CI = 1.09-2.66, P = .022) and invasive EEG monitoring (HR = 1.97, 95% CI = 1.04-3.74, P = .039) were significantly associated with shorter time to seizure recurrence. Performing MR-guided laser ablation or radiofrequency ablation instead of open resection (OR = 2.05, 95% CI = 1.08-3.89, P = .028) was independently associated with suboptimal or poor seizure outcome (Engel II-IV) at last follow-up. Postoperative neurological complications occurred in 42.5% of patients, most commonly motor deficits (29.9%). Permanent neurological complications occurred in 7.8% of surgeries, including 5% and 1.4% rate of permanent motor deficits and dysphasia, respectively. Resection of the frontal operculum was independently associated with greater odds of motor deficits (OR = 2.75, 95% CI = 1.46-5.15, P = .002). Dominant-hemisphere resections were independently associated with dysphasia (OR = 13.09, 95% CI = 2.22-77.14, P = .005) albeit none of the observed language deficits were permanent. Surgery for IE is associated with a good efficacy/safety profile. Most patients experience seizure freedom, and neurological deficits are predominantly transient. Pediatric patients and those requiring invasive monitoring or undergoing stereotactic ablation procedures experience lower rates of seizure freedom. Transgression of the frontal operculum should be avoided if it is not deemed part of the epileptogenic zone. Well-selected candidates undergoing dominant-hemisphere resection are more likely to exhibit transient language deficits; however, the risk of permanent deficit is very low.

Benefits and Risks of Epilepsy Surgery in Patients With Focal Cortical Dysplasia Type 2 in the Central Region.

BACKGROUND AND OBJECTIVES: Focal cortical dysplasia type 2 (FCD2) in the central region can cause drug-resistant epilepsy for which surgery remains challenging because of subsequent functional deficits. Advances in imaging and surgical techniques have progressively improved outcome. We aimed to assess the benefits on epilepsy and the functional risks after FCD2 resections in these highly eloquent areas. METHODS: We retrospectively studied all consecutive patients with histologically confirmed FCD2 located in the central region operated on between 2000 and 2019 at a single center. We analyzed electroclinical and imaging features (including fMRI), seizure outcome, and early and late postoperative neurologic status correlating to anatomo-functional areas (primary motor cortex [PMC], paracentral lobule [PCL], supplementary motor area [SMA], precentral gyrus [PrCG], postcentral gyrus [PoCG], central operculum [COp]). RESULTS: Sixty patients (35 female, age 7-65 years) were included in the study. Epilepsy was characterized by early onset, high seizure frequency with clusters (30-90/d), drop attacks, and status epilepticus. Ictal semiology included sensory-motor auras, motor and postural manifestations, and postictal motor deficits. EEG and stereo-EEG patterns were like those typically recorded in FCD2. MRI was positive in 63% and 18F-fluorodeoxyglucose-PET was positive in 86% of the patients. fMRI demonstrated activations close to the FCD2 (59%) or minor reorganization (41%) but none within the lesion. Seizure-free outcome (2- to 20-year follow-up) was obtained in 53 patients (88%), including 37 achieving Engel class IA (62%), correlating with complete FCD2 removal. Early transitory postoperative deficits occurred in 52 patients (87%), which were severe in 19, mostly after PMC, PCL, and SMA resections, while PrCG, PoCG, and COp resections were associated with minor/moderate deficits. Total recovery was observed in 21 of 52 patients (40%), while a permanent deficit (>2 years) persisted in 31 (minor 19, moderate 9, major 3). The best outcome (seizure freedom without deficit [48%] or with minor deficit (28%]) was significantly more frequent in children (p = 0.025). Antiseizure medications were discontinued in 28 patients (47%). Quality of life correlated with seizure-free outcome and absence of postoperative deficit; 43 patients (72%) reported a schooling or socio-professional improvement. DISCUSSION: Excellent seizure outcome and low rates of major permanent disability can be achieved after central FCD2 resections despite functional risks. CLASSIFICATION OF EVIDENCE: Due to its retrospective nature, this study provides Class IV evidence that good seizure outcomes with minor additional deficits can be achieved after epilepsy surgery in the central region.

18F-FDG PET/MR in focal epilepsy: A new step for improving the detection of epileptogenic lesions.

PURPOSE: Hybrid PET/MR is a promising tool in focal drug-resistant epilepsy, however the additional value for the detection of epileptogenic lesions and surgical decision-making remains to be established. METHODS: We retrospectively compared 18F-FDG PET/MR images with those obtained by a previous 18F-FDG PET co-registered with MRI (PET+MR) in 25 consecutive patients (16 females, 13-60 years) investigated for focal drug-resistant epilepsy. Visual analysis was performed by two readers blinded from imaging modalities, asked to assess the technical characteristics (co-registration, quality of images), the confidence in results, the location of PET abnormalities and the presence of a structural lesion on MRI. Clinical impact on surgical strategy and outcome was assessed independently. RESULTS: The location of epileptic focus was temporal in 9 patients and extra-temporal in 16 others. MRI was initially considered negative in 21 patients. PET stand-alone demonstrated metabolic abnormalities in 19 cases (76%), and the co-registration with MRI allowed the detection of 4 additional structural lesions. Compared to PET+MR, the PET/MR sensitivity was increased by 13% and new structural lesions (mainly focal cortical dysplasias) were detected in 6 patients (24%). Change of surgical decision-making was substantial for 10 patients (40%), consisting in avoiding invasive monitoring in 6 patients and modifying the planning in 4 others. Seizure-free outcome (follow-up>1 year) was obtained in 12/14 patients who underwent a cortical resection. CONCLUSION: Hybrid PET/MR may improve the detection of epileptogenic lesions, allowing to optimize the presurgical work-up and to increase the proportion of successful surgery even in the more complex cases.

The Effectiveness of Vagus Nerve Stimulation in Drug-Resistant Epilepsy Correlates with Vagus Nerve Stimulation-Induced Electroencephalography Desynchronization.

Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated "ON" and nonstimulated "OFF" periods and between responder (R) and nonresponder (NR) patients. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during "ON" and "OFF" periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients. Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity. Impact statement Electroencephalography (EEG) desynchronization has been proposed to be a mechanism for antiepileptic effect of vagus nerve stimulation (VNS). We measured interictal EEG time-series synchronization during stimulated (ON) and nonstimulated (OFF) periods in epileptic patients treated by VNS. Phase lag index differences between ON and OFF periods were measured in delta, theta, and beta bands only in responder patients. To our knowledge, our study is the first to statistically correlate interictal cortical desynchronization during ON periods with reduction in seizure frequency. Our result supports the hypothesis that the antiseizure effect of VNS is mediated by cortical desynchronization.

Metabolic correlates of cognitive impairment in mesial temporal lobe epilepsy.

PURPOSE: The purpose of the study was to determine the correlations between brain metabolism and cognitive impairment in patients with drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: [18F]-FluoroDeoxyGlucose positron emission tomography ([18F]-FDG-PET) and neuropsychological assessment were performed in 97 patients with MTLE (53 females, 15-56 years old, mean: 31.6 years, standard deviation (SD) = 10.4) with unilateral hippocampal sclerosis (HS, 49 left). We compared brain metabolism and gray matter volume (GMV) between patients with cognitive impairment (intelligence quotient (IQ) and memory index <80) and patients with normal cognition, using statistical parametric mapping (SPM), in the whole population then in right and left HS (RHS, LHS) separately. RESULTS: Intelligence quotient (40-121, mean: 83.7 ±â€¯16.9) and memory index (45-133, mean: 80.7 ±â€¯19.3) were impaired in 43% and 51% of the patients, respectively, similarly in RHS and LHS. We did not find any correlations between IQ and clinical factors related to epilepsy; however, there was a significant correlation between low memory index and early age of onset in LHS (p = 0.021), and widespread epileptogenic zone in the whole population (p = 0.033). Impaired IQ correlated with extratemporal hypometabolism, involving frontoparietal networks implicated in the default mode network (DMN), predominantly in the midline cortices. Metabolic asymmetry regarding HS lateralization included the precuneus (pC) in LHS and the anterior cingulate cortex (ACC) in RHS, both areas corresponding to key nodes of the DMN. Memory index correlated with the same frontoparietal networks as for IQ, with an additional involvement of the temporal lobes, which was ipsilateral in RHS and contralateral in LHS. A diffuse decrease of GMV including the ipsilateral hippocampus correlated with cognitive impairment; however, the structural alterations did not match with the hypometabolic areas. CONCLUSIONS: Cognitive impairment in MTLE correlates with extratemporal hypometabolism, involving the mesial frontoparietal networks implicated in the DMN and suggesting a disconnection with the affected hippocampus. Asymmetric alterations of connectivity may sustain the predominant ACC and pC metabolic decrease in patients with cognitive impairment.

Sleep related epilepsy in focal cortical dysplasia type 2: Insights from sleep recordings in presurgical evaluation.

OBJECTIVE: To determine the relationship between seizure onset, sleep stage and focal cortical dysplasia type 2 (FCD2) location in sleep related epilepsy (SRE). METHODS: We reviewed scalp video-EEG data of 77 patients with SRE among 130 surgically treated patients with histologically confirmed FCD2. Seizure onset was classified as occurring during NREM, REM and after arousal. RESULTS: Sleep recordings were available for 65 patients (37 males, 7-49 years old). FCD2 was located in frontal lobe in 46 (71%) and in extra-frontal regions in 19, including the temporal lobe in 6. MRI was negative/doubtful in 35 cases. Interictal rhythmic/pseudorhythmic spike rate increased from 31% during waking to 65% during sleep. Seizure onset occurred from NREM in 46 cases (71%), mostly from stage 2, and after arousal in 14 (22%). Seizures occurring from NREM/REM sleep were significantly more frequent in frontal (89%) compared to extra-frontal location (42%), whilst arousal preceded seizure onset more often in extra-frontal (58%) compared to frontal location (7%). CONCLUSIONS: NREM seizure onset is the most common ictal pattern in SRE due to frontal FCD2 whereas preceding arousal points to extra-frontal regions. SIGNIFICANCE: Sleep recordings may help for FCD2 localisation and suggest topography dependent impact on sleep related epileptic networks.

Stereotactic thermocoagulation for insular epilepsy: Lessons from successes and failures.

OBJECTIVE: To assess factors associated with favorable outcome in refractory insular epilepsy treated by volume-based stereotactic radiofrequency thermocoagulation (RFTC). METHODS: We performed volume-based RFTC in 19 patients (11 males, 7-44 years old). The volume for thermocoagulation was identified by multimodal data including electroencephalography (EEG)-video, magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (PET) in all patients, and epileptogenic zone (EZ) was assessed by stereo-electroencephalography (SEEG) in 16. MRI showed insular lesions in four patients (benign tumors, n = 2; focal cortical dysplasia [FCD], n = 1; polymicrogyria, n = 1). MRI was negative in 15 cases; however, PET was positive in 18, and FCD pattern was detected by SEEG in nine cases. The dominant hemisphere was involved in 12 cases. RFTC was performed as a separate procedure after SEEG, or as a single MRI-guided procedure. The insular volume to be coagulated was determined by a tridimensional identification of the epileptogenic cortex using MRI, PET, and SEEG, and was destroyed with coalescent thermal lesions. RESULTS: Seizure-free outcome was achieved in 10 patients (53%), including Engel class IA in three (follow-up = 1-12 years, mean = 5.4). The responder rate (including Engel classes I-III) was 89%. Transient postoperative deficits (mild hemiparesia, dysarthria, hypoesthesia, dysgeusia) were observed in eight patients (42%), with rapid and total recovery in all but one with persistent mild dysarthria. Neurological deficits were related to higher number of RFTC procedures (P = .036) and greater volume of RFTC (P = .028). Neuropsychological status was unchanged or improved in all; however, psychiatric status transitorily worsened in three patients. Factors contributing to seizure-free outcome were the detection of FCD pattern (P = .009), localized EZ (P = .038), low RFTC volume (P = .002), low number of RFTC procedures (P = .001), and low RFTC volume/number ratio (P = .012). Optimal volume of RFTC around 2 cm3 offered the best compromise between efficacy and safety. SIGNIFICANCE: RFTC may be curative in insular epilepsy after accurate localization of EZ with SEEG. Best outcome was associated with low volume of thermolesions.

Hypoxemia following generalized convulsive seizures: Risk factors and effect of oxygen therapy.

OBJECTIVE: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS). METHODS: We reviewed the video-EEG recordings of 1,006 patients with drug-resistant focal epilepsy included in the REPO2MSE study to identify those with ≥1 GCS and pulse oximetry (SpO2) measurement. Factors determining recovery of SpO2 ≥ 90% were investigated using Cox proportional hazards models. Association between SpO2 nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS: A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 GCS (86%). Rate of GCS with SpO2 <70% dropped from 40% to 21% when oxygen was administered early (p = 0.046). Early recovery of SpO2 ≥90% was associated with early administration of oxygen (p = 0.004), absence of postictal generalized EEG suppression (PGES) (p = 0.014), and extratemporal lobe epilepsy (p = 0.001). Lack of early administration of O2 (p = 0.003), occurrence of PGES (p = 0.018), and occurrence of ictal hypoxemia during the focal phase (p = 0.022) were associated with lower SpO2 nadir. CONCLUSION: Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.

Correction to: 18F-FDG PET in drug-resistant epilepsy due to focal cortical dysplasia type 2: additional value of electroclinical data and coregistration with MRI.

The original version of this article has added numbers in the text which are unnecessary. Correct line should be: "We also performed PET/MRI based surgical resections in an increasing number of MRI negative/ doubtful cases with favourable outcome."

18F-FDG PET in drug-resistant epilepsy due to focal cortical dysplasia type 2: additional value of electroclinical data and coregistration with MRI.

PURPOSE: To assess the localizing value of 18F-FDG PET in patients operated on for drug-resistant epilepsy due to focal cortical dysplasia type 2 (FCD2). METHODS: We analysed 18F-FDG PET scans from 103 consecutive patients (52 males, 7-65 years old) with histologically proven FCD2. PET and MRI data were first reviewed by visual analysis blinded to clinical information and FCD2 location. The additional value of electroclinical data and PET/MRI coregistration was assessed by comparison with pathological results and surgical outcomes. RESULTS: Visual analysis of PET scans showed focal or regional hypometabolism corresponding to the FCD2 in 45 patients (44%), but the findings were doubtful or misleading in 37 patients and negative in 21. When considering electroclinical data, positive localization was obtained in 73 patients, and this increased to 85 (83%) after coregistration of PET and MRI data. Under the same conditions, MRI was positive in 61 patients (59%), doubtful in 15 and negative in 27. The additional value of PET was predominant in patients negative or doubtful on MRI, localizing the FCD2 in 35 patients (83%). Interobserver agreement correlated with the grade of hypometabolism: it was good in patients with mild to severe hypometabolism (82-95%), but moderate in those with subtle/doubtful hypometabolism (45%). The main factors influencing positive PET localization were the grade of hypometabolism and the size of the FCD2 (P < 0.0001). Misleading location (nine patients) was associated with a small FCD2 in the mesial frontal and central regions. Following limited cortical resection mainly located in extratemporal areas (mean follow-up 5.6 years), a seizure-free outcome was achieved in 94% of patients, including Engel's class IA in 72%. CONCLUSION: In this series, 18F-FDG PET contributed to the localization of FCD2 in 83% of patients. This high localizing value was obtained by integration of electroclinical data and PET/MRI coregistration. This approach may help improve the surgical outcome in extratemporal epilepsy, even in patients negative on MRI.

Planning and management of SEEG.

Stereoelectroencephalography (SEEG) aims to define the epileptogenic zone (EZ), to study its relationship with functional areas and the causal lesion and to evaluate the possibility of surgical therapy. Planning of exploration is based on the validity of the hypotheses developed from electroclinical and imaging correlations. Further investigations can refine the implantation plan (e.g. fluorodeoxyglucose positron emission tomography [FDG-PET], single photon emission computerized tomography [SPECT], magnetoencephalography [MEG] and high resolution electroencephalography [EEG-HR]). The scheme is individualized according to the features of each clinical case, but a general approach can be systematized according to the regions involved (temporal versus extra-temporal), the existence of a lesion, its type and extent. It takes account of the hemispheric dominance for language if this can be determined. In "temporal plus" epilepsies, perisylvian and insular regions are among the key structures to investigate in addition to mesial and neocortical temporal areas. In frontal lobe epilepsies, determining the functional and anatomical organization of seizures (anterior versus posterior, mesial versus dorsolateral) allows better targeting of the implantation. Posterior epilepsies tend to have a complex organization leading to multilobar and often bilateral explorations. In lesional cases, it may be useful to implant one or several intralesional electrode(s), except in cases of vascular lesions or cyst. The strategy of implantation can be modified if thermocoagulations are considered. The management of SEEG implies continuous monitoring in a dedicated environment to determine the EZ with optimal safety conditions. This methodology includes spontaneous seizure recordings, low and high frequency stimulations and, if possible, sleep recording. SEEG is applicable in children, even the very young. Specific training of medical and paramedical teams is required.

French guidelines on stereoelectroencephalography (SEEG).

Stereoelectroencephalography (SEEG) was designed and developed in the 1960s in France by J. Talairach and J. Bancaud. It is an invasive method of exploration for drug-resistant focal epilepsies, offering the advantage of a tridimensional and temporally precise study of the epileptic discharge. It allows anatomo-electrical correlations and tailored surgeries. Whereas this method has been used for decades by experts in a limited number of European centers, the last ten years have seen increasing worldwide spread of its use. Moreover in current practice, SEEG is not only a diagnostic tool but also offers a therapeutic option, i.e., thermocoagulation. In order to propose formal guidelines for best clinical practice in SEEG, a working party was formed, composed of experts from every French centre with a large SEEG experience (those performing more than 10 SEEG per year over at least a 5 year period). This group formulated recommendations, which were graded by all participants according to established methodology. The first part of this article summarizes these within the following topics: indications and limits of SEEG; planning and management of SEEG; surgical technique; electrophysiological technical procedures; interpretation of SEEG recordings; and SEEG-guided radio frequency thermocoagulation. In the second part, those different aspects are discussed in more detail by subgroups of experts, based on existing literature and their own experience. The aim of this work is to present a consensual French approach to SEEG, which could be used as a basic document for centers using this method, particularly those who are beginning SEEG practice. These guidelines are supported by the French Clinical Neurophysiology Society and the French chapter of the International League Against Epilepsy.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Stereoelectroencephalography and surgical outcome in polymicrogyria-related epilepsy: A multicentric study.

OBJECTIVE: We aimed to (1) assess the concordance between various polymicrogyria (PMG) types and the associated epileptogenic zone (EZ), as defined by stereoelectroencephalography (SEEG), and (2) determine the postsurgical seizure outcome in PMG-related drug-resistant epilepsy. METHODS: We retrospectively analyzed 58 cases: 49 had SEEG and 39 corticectomy or hemispherotomy. RESULTS: Mean age at SEEG or surgery was 28.3 years (range, 2-50). PMG was bilateral in 9 (16%) patients and unilateral in 49, including 17 (29%) unilobar, 12 (21%) multilobar, 15 (26%) perisylvian, and only 5 (9%) hemispheric. Twenty-eight (48%) patients additionally had schizencephaly, heterotopia, or focal cortical dysplasia. The SEEG-determined EZ was fully concordant with the PMG in only 8 (16%) cases, partially concordant in 74%, and discordant in 10%. The EZ included remote cortical areas in 21 (43%) cases and was primarily localized in those in 5 (10%), all related to the mesial temporal structures. All but 1 PMG patient with corticectomy or hemispherotomy had a unilateral PMG. At last follow-up (mean, 4.6 years; range, 1-16), 28 (72%) patients remained seizure free. Shorter epilepsy duration to surgery was an independent predictor of seizure freedom. INTERPRETATION: PMG-related drug-resistant epilepsy warrants a comprehensive presurgical evaluation, including SEEG investigations in most cases, given that the EZ may only partially overlap with the PMG or include solely remote cortical areas. Seizure freedom is feasible in a large proportion of patients. PMG extent should not deter from exploring the possibility of epilepsy surgery. Our data support the early consideration of epilepsy surgery in this patient group. Ann Neurol 2017;82:781-794.