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.

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.

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.

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.

18F-FDG-PET patterns of surgical success and failure in mesial temporal lobe epilepsy.

OBJECTIVE: To search for [18F]-fluorodeoxyglucose (FDG)-PET patterns predictive of long-term prognosis in surgery for drug-resistant mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS). METHODS: We analyzed metabolic data with [18F]-FDG-PET in 97 patients with MTLE (53 female participants; age range 15-56 years) with unilateral HS (50 left) and compared the metabolic patterns, electroclinical features, and structural atrophy on MRI in patients with the best outcome after anteromesial temporal resection (Engel class IA, completely seizure-free) to those with a non-IA outcome, including suboptimal outcome and failure. Imaging processing was performed with statistical parametric mapping (SPM5). RESULTS: With a mean follow-up of >6 years (range 2-14 years), 85% of patients achieved a class I outcome, including 45% in class IA. Class IA outcome was associated with a focal anteromesial temporal hypometabolism, whereas non-IA outcome correlated with extratemporal metabolic changes that differed according to the lateralization: ipsilateral mesial frontal and perisylvian hypometabolism in right HS and contralateral fronto-insular hypometabolism and posterior white matter hypermetabolism in left HS. Suboptimal outcome presented a metabolic pattern similar to the best outcome but with a larger involvement of extratemporal areas, including the contralateral side in left HS. Failure was characterized by a mild temporal involvement sparing the hippocampus and relatively high extratemporal hypometabolism on both sides. These findings were concordant with electroclinical features reflecting the organization of the epileptogenic zone but were independent of the structural abnormalities detected on MRI. CONCLUSIONS: [18F]-FDG-PET patterns help refine the prognostic factors in MTLE and should be implemented in predictive models for epilepsy surgery.

Vagus Nerve Stimulation Removal or Replacement Involving the Lead and the Electrode: Surgical Technique, Institutional Experience and Outcome.

OBJECTIVE: To analyze the outcome of epileptic patients who had redo surgery involving the vagus nerve stimulation's lead. METHODS: We reviewed the clinical and surgical records of all patients who had a complete vagus nerve stimulation (VNS) removal or replacement or any redo surgical procedure involving the system lead at Sainte-Anne Hospital in Paris, France. RESULTS: Between the years 1999 and 2016, 41 redo surgical procedures involving the lead or electrode were achieved, of which 23 were complete VNS explantations, 12 were complete system replacements, 5 were lead changes only, and 1 was isolated lead removal. 41% of the surgical procedures were achieved in female patients. This population has a median age at VNS implantation of 33.6 years (interquartile range [IQR], [21.4-38.6]. Median time between the VNS implantation and the redo surgery involving the lead was 4.9 years (IQR, 2.9-8). The reason for VNS removal was mainly a lack of clinical effectiveness. No preoperative or postoperative complications occurred after complete VNS system removal or lead replacement. The effectiveness of the VNS therapy remained unchanged after lead replacement. No vagus nerve injury was reported, nor did symptoms suggest that it was disabled. CONCLUSIONS: Complete removal or replacement of the VNS system including the lead and the electrode is feasible and safe. These procedures should be offered to patients who would no longer benefit from the VNS or when only a lead change is needed.

Epilepsy surgery / Chirurgie de l'épilepsie

Epilepsy surgery. Epilepsy surgery is indicated for adults or children with partial, drug-resistant and disabling epilepsy. It has developed over the last few decades through better identification of candidates, advances in imaging and surgical techniques. Main indications are temporal lobe epilepsy associated with hippocampal sclerosis, low-grade glial tumors and focal cortical dysplasia. Pre-surgical assessment is based on clinical, neurophysiological and imaging data which most often allow to carry the surgical indication. A neuropsychological and psychiatric assessment is essential to investigate the comorbidities and evaluate the risk of post-operative decompensation. Intracerebral exploration using stereotactic implanted electrodes (stereo-electroencephalography) may be necessary to identify the epileptogenic zone and define the surgical strategy. Resection surgery (corticectomy or lesionectomy) is the most common procedure. Seizure-free outcome is obtained in 60-80% of patients after surgery, with a low morbidity. These results are maintained over the long term and associated by an improvement in the quality of life and a reduction in the costs of the disease. Best results are observed in young subjects with short epilepsy duration.

Chirurgie de l'épilepsie. La chirurgie de l'épilepsie s'adresse aux patients adultes ou enfants souffrant d'une épilepsie partielle pharmacorésistante et invalidante. Elle s'est développée au cours des dernières décennies grâce à une meilleure identification des candidats, aux progrès de l'imagerie et des techniques chirurgicales. Les principales indications sont représentées par l'épilepsie temporale associée à une sclérose hippocampique, les tumeurs gliales de bas grade et les dysplasies corticales focales. Le bilan préchirurgical repose sur des données cliniques, neurophysiologiques et d'imagerie qui permettent le plus souvent de porter l'indication opératoire. Une évaluation neuropsychologique et psychiatrique est indispensable afin de rechercher les comorbidités et d'évaluer le risque de décompensation postopératoire. Une exploration intracérébrale par électrodes implantées en conditions stéréotaxiques (stéréo-électroencéphalographie) peut être nécessaire pour identifier la zone épileptogène et définir la stratégie chirurgicale. Les interventions de résection sont les plus courantes (cortectomie ou lésionectomie). La suppression des crises est obtenue chez 60 à 80 % des patients au prix d'une faible morbidité. Ces résultats se maintiennent à long terme et s'accompagnent d'une amélioration de la qualité de vie et d'une réduction des coûts de la maladie. Les meilleurs résultats sont obtenus chez les sujets jeunes avec une faible durée de l'épilepsie.

Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study.

OBJECTIVE: Despite its well-known effectiveness, the cost-effectiveness of epilepsy surgery has never been demonstrated in France. We compared cost-effectiveness between resective surgery and medical therapy in a controlled cohort of adult patients with partial intractable epilepsy. METHODS: A prospective cohort of adult patients with surgically remediable and medically intractable partial epilepsy was followed over 5 years in the 15 French centers. Effectiveness was defined as 1 year without a seizure, based on the International League Against Epilepsy (ILAE) classification. Clinical outcomes and direct costs were compared between surgical and medical groups. Long-term direct costs and effectiveness were extrapolated over the patients' lifetimes with a Monte-Carlo simulation using a Markov model, and an incremental cost-effectiveness ratio (ICER) was computed. Indirect costs were also evaluated. RESULTS: Among the 289 enrolled surgery candidates, 207 were operable-119 in the surgical group and 88 in the medical group-65 were not operable and not analyzed here, 7 were finally not eligible, and 10 were not followed. The proportion of patients completely seizure-free during the last 12 months (ILAE class 1) was 69.0% in the operated group and 12.3% in the medical group during the second year (p < 0.001), and it was respectively 76.8% and 21% during the fifth year (p < 0.001). Direct costs became significantly lower in the surgical group the third year after surgery, as a result of less antiepileptic drug use. The value of the discounted ICER was 10,406 (95% confidence interval [CI] 10,182-10,634) at 2 years and 2,630 (CI 95% 2,549-2,713) at 5 years. Surgery became cost-effective between 9 and 10 years after surgery, and even earlier if indirect costs were taken into account as well. SIGNIFICANCE: Our study suggests that in addition to being safe and effective, resective surgery of epilepsy is cost-effective in the medium term. It should therefore be considered earlier in the development of epilepsy.

Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.

OBJECTIVE: The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum. METHODS: We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants. RESULTS: We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP). SIGNIFICANCE: GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.