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.

Hypothalamic hamartoma associated with polymicrogyria and periventricular nodular heterotopia in children: report of three cases and discussion of the origin of the seizures.

PURPOSE: Hypothalamic hamartomas (HH) are malformations responsible for drug-resistant epilepsy. HH are usually isolated or part of a genetic syndrome, such as Pallister-Hall. Exceptionally they can be associated with other brain malformations such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH). We discuss the origin of the seizures associated with this combination of malformations, through electrophysiological studies, and review the literature on this rarely reported syndrome. METHODS: We retrospectively reviewed the patients with HH who had surgery between 1998 and 2020 and selected those with associated focal PMG and PNH, detected on MRIs. All patients had comprehensive clinical evaluation and surface video-EEG and one underwent stereoelectroencephalography (SEEG). RESULTS: Three male patients out of 182 were identified with a mean age at surgery of 7.5 years. MRI showed unilateral focal PMG (fronto-insulo-parietal, fronto-insulo-parieto-opercular, and fronto-insular, respectively) and multiple PNH homolateral to the main HH implantation side. In two patients, there were strong clinical and scalp EEG arguments for seizure onset within the HH. In the third, due to abnormalities on scalp video-EEG in the same area as PMG and the lack of gelastic seizures, SEEG was indicated and demonstrated seizure onset within the hamartoma. With a mean follow-up of 6 years, two patients were seizure-free. CONCLUSION: Our results show that HH is the trigger of epilepsy, which confirms the high epileptogenic potential of this malformation. In patients such as ours, as in those with isolated HH, we recommend to begin by operating the HH independently of seizure semiology or electrophysiological abnormalities.

Hippocampal sclerosis and epilepsy surgery in neurofibromatosis type 1: case report of a 3-year-old child explored by SEEG and review of the literature.

PURPOSE: Epilepsy associated with neurofibromatosis type 1 (NF1) is infrequent and usually controlled with anti-epileptic drugs. However, in some drug-resistant patients a presurgical evaluation should be considered. Hippocampal sclerosis (HS) is one of the rare causes of epilepsy in neurofibromatosis type 1, which can lead to surgery. METHODS: We present a three-year-old child with refractory epilepsy associated with several structural brain abnormalities but normal hippocampi on brain MRI and a heterozygous variant in the NF1 gene (c.2542G > A). A complete presurgical evaluation was performed including stereo-electroencephalography (SEEG). RESULTS: Usual seizures were recorded, and the seizure onset zone was delineated in the anterior hippocampus. Pathological examination performed after a tailored mesio-temporal resection confirmed hippocampal sclerosis, and the child achieved seizure freedom with 2 years of follow-up. CONCLUSION: This rare pediatric case illustrates that NF1 may be associated with early-onset refractory epilepsy secondary to MRI-negative HS, supporting the major role of SEEG in the presurgical evaluation of patients with extended cortical malformations.

Clinical semiology of temporal lobe seizures in preschool children: contribution of invasive recording to anatomical classification.

Focal seizure semiology is often inadequately studied, specifically in preschool children. Among drug-resistant epilepsies amenable to surgery, temporal lobe seizure semiology has been widely described in this age group. Nevertheless, a systematic anatomo-electroclinical study has never been performed. We retrospectively reviewed the charts of patients younger than six years old at the time of video-EEG recording who were operated on for temporal lobe epilepsy in our centre between 2010 and 2016. In order to describe the electroclinical semiology and establish anatomo-clinical correlations, we reviewed all the recorded seizures on scalp and invasive video-EEG and analysed pre- and postsurgical clinical data, MRI scans, and surgical and pathological data. We classified patients into the following four anatomical groups: mesio-temporal, temporal lateral, polar, and mesio-lateral, and for each group we selected video-EEG samples for educational purposes. Twenty-eight patients fulfilled the selection criteria. Twenty-three patients (82%) were explored with invasive electrodes that consisted of foramen ovale electrodes in 11 (39%) and stereoelectroencephalography in 12 (43%). The majority of the 53% of patients with mesio-temporal epilepsies had specific ictal semiology, as described in adults. The others had subtle seizures or seizures limited to apnoea. The other groups also had some features comparable to adults, although no child reported the classic auras of lateral epilepsies. In total, 11% had infantile spasms (IS); post-ictal examination provided lateralization signs in 28%. With a mean post-surgical follow-up duration of 5.5 years, 89% of the patients were classified as Engel Class I. Preschool children were shown to have non-specific seizures, notably subtle events or IS. However, careful video-EEG analysis can provide arguments for localizing the epileptogenic zone within the temporal lobe in most cases. Seizures with apnoea are characteristic of mesial temporal onset in patients with long-term epilepsy-associated tumours.

18 F-FDG-PET hypometabolic pattern reveals multifocal epileptic foci despite limited unique stereotyped seizures.

PURPOSE: Interictal positron emission tomography (PET) with 18F-FDG has largely proved its utility in presurgical evaluation of drug-resistant epilepsies (DRE) and in the surgical outcomes. Interictal hypometabolism topography is related to the neuronal networks involved in the seizure onset zone (SOZ) and spread pathways. 18F-FDG PET has a good prognostic value for post-surgical outcome, especially in cases with unique focal ictal semiology and a limited extent of hypometabolism. Surprisingly few patients have similar limited ictal features but extended hypometabolism. The objective of this study is to show that stereoelectro encephalography (SEEG) provides an explanation for this large hypometabolism, which impacts the surgical strategy. METHODS: A cohort of 248 patients underwent 18F-FDG PET and SEEG to explore for refractory epilepsy in two close tertiary epilepsy centers between January 2009 and December 2017. From this cohort, a subset of patients was selected with extended PET metabolism despite showing unique and limited ictal features in scalp EEG. The surgical outcome of this subset of patients has been analysed with respect to their FDG-PET and SEEG to understand the relationship between PET/SEEG/ presentation and surgical outcome. RESULTS: We report a series of seven patients with DRE and unique stereotyped ictal semiology but extensive 18F-FDG-PET hypometabolism revealing unexpected multifocal SOZ using SEEG. All SOZ were encompassed by the hypometabolic area. CONCLUSION: Our results demonstrate the necessity of accounting for the discrepancy between limited symptoms and widespread hypometabolism which can reveal multifocal SOZ. In those patients, surgical possibilities should be considered carefully.

Focal polymicrogyria in children: Contribution of invasive explorations and epileptogenicity mapping in the surgical decision.

OBJECTIVE: Report of the contribution of invasive EEG (iEEG) and epileptogenicity mappings (EM) in a pediatric cohort of patients with epilepsy associated with focal polymicrogyria (PMG) and candidates for resective surgery. METHOD: Retrospective pediatric case series of patients presenting focal PMG-related refractory epilepsy undergoing an invasive exploration (iEEG) at Fondation Rothschild Hospital. We reviewed clinical data, structural MRI, and visual analysis of iEEG recordings. Moreover, time-frequency analysis of SEEG signals with a neuroimaging approach (epileptogenicity maps) was used to support visual analysis. RESULTS: Between 2012 and 2019, eight patients were selected. Five patients were explored with stereoelectroencephalography (SEEG) only, one patient with subdural exploration (SDE) only and two patients first underwent SEEG and then SDE. The mean age at seizure onset was 40.3 months (range 3-120), and the mean age for the iEEG 10.8 years (range 7-15). The epileptogenic zone (EZ) appeared concordant to the PMG lesion in only one case, was larger in three cases, smaller in two cases and different in one case. Four cases were selected for tailored resective surgery and one for total callosotomy. Two patients remained seizure-free at their last follow-up (mean 32.6 months, range 7-98). Epileptogenicity mapping (EM) refined the qualitative analysis, showing in four patients an EZ larger than visually defined. CONCLUSION: This study is the first pediatric study to analyze the value of iEEG and EM as well as operability in focal PMG-related refractory epilepsy. The results illustrate the complexity of this pathology with variable concordance between the EZ and the lesion and mixed response to surgery.

Management and results of epilepsy surgery associated with acyclovir prophylaxis in four pediatric patients with drug-resistant epilepsy due to herpetic encephalitis and review of the literature.

PURPOSE: Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis in children and is responsible for epilepsy in approximately half of patients. In addition to medical treatment, epilepsy surgery may be offered to drug-resistant patients but carries a high risk of relapse of herpetic encephalitis. We are reporting our series of patients operated on between 2000 and 2019 with the systematic administration of acyclovir (ACV). RESULTS: Four pediatric patients aged 4.5-12.8 years with drug-resistant epilepsy post-HSE underwent a tailored focal resection following invasive recordings (three patients) and a complete callosotomy (one patient). The total number of the surgical procedures for the four patients was eight, and a systematic administration of ACV as a prophylactic treatment of herpetic encephalitis relapse was done at each step. No patients had a relapse and the ACV was well-tolerated in all the cases. Following surgery two patients are seizure free, the patient who underwent callosotomy is Engel 3 and the fourth patient, in whom a large epileptic zone has contraindicated a second surgery, is Engel 4. CONCLUSIONS: Our series demonstrated the dramatic efficacy of systematic ACV prophylaxis during all cranial surgeries. Moreover, our results on epilepsy, together with those of the literature, encourage more consideration regarding epilepsy surgery in this specific etiology. All types of surgical procedures (curative or palliative) can be offered to the patients, but in the case of focal surgery, due to the poor anatomical limits, invasive recordings are highly recommended.

Identification of TSC1 or TSC2 mutation limited to the tumor in three cases of solitary subependymal giant cell astrocytoma using next-generation sequencing technology.

PURPOSE: Subependymal giant-cell astrocytomas (SEGAs) are low grade intraventricular tumors typically found in patients with tuberous sclerosis complex (TSC). The occurrence of SEGA in non TSC patients is very rare and from a genetic point of view these so-called solitary SEGA are thought to result either from somatic mutations in one of the TSC genes (TSC1 or TSC2) limited to the tumor, or be part of a "forme fruste" of TSC with somatic mosaicism. We report on three new cases of solitary SEGA with germline and somatic mutation analysis. METHODS: We retrospectively analyzed TSC genes in three patients with a solitary SEGA using next-generation sequencing technique. RESULTS: In the three patients, a somatic mutation of TSC1 or TSC2 was found only in the tumor cells: one patient had a TSC1 heterozygote mutation, involving the natural acceptor splicing site of intron 15 (c.1998-1G > A (p.?). Two patients had a TSC2 mutation located in the canonical splicing donor site of intron 5 (c.599 + 1G > A) in 70% of the alleles in one patient and in exon 9: c.949_955dup7 (p.V319DfxX21) in 25 of the alleles in the second patient. No other TSC mutations were found in patient's blood or tumor and those identified mutations were absent in blood DNA from parents and siblings. CONCLUSION: We therefore conclude that solitary SEGA can occur with a TSC1 or TSC2 mutation limited to the tumor in patients without TSC.

Invasive evaluation in children (SEEG vs subdural grids).

Designed from the 60s to the 80s for adults, and despite the development of many new techniques, invasive explorations still have indications in children with focal drug-resistant epilepsy. The main types are stereoelectroencephalography (SEEG) and subdural explorations (SDE). They provide precise information on the localization of the epileptogenic zone (EZ), its relationships with eloquent cortex, and the feasibility of performing a tailored surgical resection. Thermocoagulations, which are a diagnostic and therapeutic tool, can be performed using SEEG electrodes. Both techniques are feasible in children, with an age limitation for SEEG (which requires a bone thickness above 2 mm). The complication rate is higher with SDE. Opposed for a long time and never compared in a systematic study, they should presently be considered complementary. The indications cannot be directly inferred from those for adults, as there are pediatric particularities in the seizures' semiology, functional areas, imaging and urgent situations. We successively discuss the choice in individual cases of SEEG or SDE respectively, the specific problematic in infancy and early childhood, the schema in SEEG for cryptogenic epilepsies (in particular insular), the particularities of polymicrogyria and deeply located lesions, and finally, SEEG designed for thermocoagulations. Future improvements should include more accurate implantation schemas thanks to advanced non-invasive explorations and possibilities to perform SEEG in infants.

Seizure outcome and prognostic factors for surgical management of hypothalamic hamartomas in children.

PURPOSE: Hypothalamic hamartomas (HH) are rare benign lesions frequently associated with gelastic seizures early in life. Epilepsy can progress to multiple seizure types with cognitive impairment and behavioural disturbance, leading in some cases to epileptic encephalopathy. METHODS: We reviewed a retrospective series of 112 children treated in a single center, between 1998 and 2017. RESULTS: According to Delalande's HH classification, type1 was found in 2 patients, type 2 in 67, type 3 in 31, and type 4 in 12 patients. Stereotactic endoscopic disconnection was performed in 92 % of the procedures. Median age at diagnosis was 40 months and 7.6 years at surgery. Median time between diagnosis and surgery was 31 months and median follow up 4.1 years. For all HH types, 77.6 % of the patients had a favourable outcome (Engel I + II outcome score) with 57.1 % seizure-free (Engel I). The best outcome was obtained in patients with type 2 HH, (68.7 % Engel I and 85.1 % Engel I + II). The overall complication rate was 8.3 %, which is in line with previous series. Patients with isolated gelastic seizures had a better outcome (Engel I + II in 90 %), as compared to those with other seizure types (p = 0.07). A short delay between hamartoma diagnosis and surgery was a statistically significant factor for a good outcome (p = 0.03). CONCLUSION: Patients with HH and drug-resistant epilepsy should be early identified in order to propose surgical treatment without delay. Endoscopic disconnection is a safe and efficacious surgical option with good seizure outcome and immediate treatment results.

Dissecting the genetic basis of focal cortical dysplasia: a large cohort study.

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.

Parasagittal hemispherotomy in hemispheric polymicrogyria with electrical status epilepticus during slow sleep: Indications, results and follow-up.

PURPOSE: Polymicrogyria (PMG), although the most common brain malformation, represents a low percentage among patients operated on for epilepsy. In cases of hemispheric PMG, electrical status epilepticus during slow sleep (ESESS) may occur leading to an aggravation of the neurological condition and a risk of drug resistance. In such cases, surgical treatment can be offered. METHODS: From a population of 230 children who underwent hemispherotomy for epilepsy, we retrospectively reviewed the patients with unilateral PMG and drug-resistant ESESS focusing on clinical charts, electrophysiological data and post-surgical outcome. RESULTS: Eighteen patients were operated on at a mean age of 7.2 years. The average age was 2 years at seizure onset and 4.4 years at diagnosis of ESESS. All the patients preoperatively had some degree of developmental delay associated with a hemiparesis. During ESESS all of them evidenced a cognitive decline and eight experienced a worsening of the hemiparesis; ESESS was resistant to at least three antiepileptic drugs. The outcome of epilepsy, with a mean follow-up of 12.8 years showed that ESESS disappeared in all patients while 16 of 18 became seizure-free. An improvement of behavior and cognitive condition was observed in all. CONCLUSION: Hemispherotomy can be helpful in patients with drug-resistant ESESS and hemispheric PMG while keeping in mind that more often an accurate medical treatment can be sufficient. The main benefit of surgery is to definitively stop the seizures and to withdraw the medical treatment while keeping in mind the risk of motor aggravation.

SEEG-guided radiofrequency thermocoagulation of epileptic foci in the paediatric population: Feasibility, safety and efficacy.

PURPOSE: Focal epilepsy in children may be refractory to pharmacological treatment and surgical resection may be an appropriate option. When invasive electroencephalogram is required in the presurgical evaluation, depth electrodes can be used to create focal lesions in the epileptogenic zone using radiofrequency thermocoagulation (RFTC), to disrupt the epileptogenic zone. METHODS: This study aimed to assess the efficacy and safety of RFTC in a paediatric population of 46 patients. RESULTS: The mean age of onset was 3.3 years and the mean age at SEEG was 8.2 years. MRI lesions were identified in 71.7% of the series, among them 60% of malformation of cortical development. 43.5% of the patients were seizure free at 1 month, 26.1% were responders. The mean duration of improvement was 6.8 months. 8 children were seizure free for >8 months and among them, 6 are currently seizure free for 8-24 months. 5 patients had functional deficits post-procedures, transient in 4 patients and prolonged in one of whom. 3/5 were anticipated following the results of cortical stimulation. Multivariate analysis found 3 independent criteria linked to RFTC efficiency one month after RFTC: frequency of the seizures before RFTC, age and number of contacts used. CONCLUSION: RFTC is a safe method for the paediatric population providing important predictive information for surgical resection. An improvement in seizure frequency, often transient, is seen in 2/3 of our patients. RTFC could be useful as a palliative technique for children with an epileptogenic zone overlapping with eloquent areas, with minimal risk of sequelae.

Investigation of paediatric occipital epilepsy using stereo-EEG reveals a better surgical outcome than in adults, especially when the supracalcarine area is affected.

Occipital epilepsy is the least common among surgical series because: (1) the location makes it hard to asses by EEG; (2) the seizure semiology often reflects propagation; and (3) surgery entails a high risk of neurological deficits. In children, subjective symptoms are harder to assess, adding to the difficulty of a proper diagnosis. We aimed to determine electroclinical characteristics of occipital lobe epilepsy in a paediatric population by reviewing 20 children between one and 16 years, who had undergone intracranial recordings with depth electrodes. Eight patients had pure occipital epilepsies and 12 had "occipital plus" epilepsies. We identified four different seizure spreading patterns: (1) pure occipital (40%) with oculomotor symptoms; (2) temporal (30%) with hypomotor behaviour and automatisms; (3) frontal (20%) with movements of the limbs; and (4) spasms (10%). Two thirds of the children above 11 years reported visual aura, but this was probably underestimated in younger children as some seizures began with non-specific motion arrest. Automatisms were only observed when the lateral temporal lobe was involved. Patients with a pure occipital form had a seizure onset zone strictly in the occipital lobe. Lingual and cuneus gyri were the most epileptogenic structures. Scalp EEG showed diffuse EEG abnormalities in two thirds of the patients and 25% of these led to false lateralization of the SOZ. Although MRI lesions were always visible, imaging and scalp EEG could be misleading and often not sufficient to guide surgery. After surgery, 68% of the patients were classified as Engel Class I, and surgical outcome was even better for patients in whom the supracalcarine area was affected, with 87.5% reaching seizure freedom. Seizure spread patterns in occipital epilepsy are similar in paediatric and adult populations, even though it is often impossible to obtain subjective symptoms in children. Postsurgical outcome is better than in adults, especially in patients in whom the supracalcarine area is affected.

Refractory epilepsy in preschool children with tuberous sclerosis complex: Early surgical treatment and outcome.

PURPOSE: Epilepsy surgery has been shown to be effective in treating focal epilepsy related to tuberous sclerosis complex (TSC). We analyzed the advantage of early surgical management in terms of seizure frequency and development. METHOD: We retrospectively studied the 15 patients younger than 6 years who underwent resective surgery between 2006 and 2016. Fourteen of them had invasive monitoring while the 15th was operated on under corticography. RESULTS: Epilepsy began before 5 months of age in all patients. Overall 13 patients (86%) had a dramatic improvement of epilepsy after surgery (Engel 1 and 2) including 9 patients (60%) seizure free (Engel 1 A). In the group of 9 patients younger than 20 months at the time of surgery who presented with catastrophic epilepsies, 77% are Engel 1 A and the other 23% Engel 2. In this subpopulation, no one developed autism and four (44%) regained normal development. CONCLUSIONS: In early onset epilepsies associated with TSC, surgical treatment is highly effective, in particular when performed early. Invasive monitoring contributes to the successful outcome. Those data have to be confirmed by multicentric studies including quantitative analyses of the recordings.

Surgery for subependymal giant cell astrocytomas in children with tuberous sclerosis complex.

OBJECTIVE: Subependymal giant cell astrocytomas (SEGAs) are low-grade intraventricular glial tumors that develop in 10-15% of patients with tuberous sclerosis complex; they often cause hydrocephalus and are potentially accessible to a surgical treatment. Our aim is to evaluate morbidity and results after surgery in symptomatic and asymptomatic patients. METHOD: We present a retrospective series of 18 pediatric patients operated on for SEGA between 2006 and 2016 at our institution. We reviewed surgical indications, preoperative clinical and radiologic data, surgical management, and clinical and radiological follow-up. RESULTS: Mean age at surgery was 10.7 years. The surgical decision was based on clinical signs of raised intracranial pressure due to hydrocephalus in 8 and on radiological findings without any clinical signs in the other 10 patients (increased in SEGA volume with or without ventricular enlargement). Surgical treatment consisted in a frontal trans-ventricular microsurgical approach in 17 patients and an endoscopic approach in 1. External ventricular drainage was placed in all the patients but 1. Ventriculoperitoneal shunting (VPS) became necessary in 6 patients, all of them presenting with a preoperative active hydrocephalus. Morbidity appeared very low with meningitis occurring in 1 patient. Resection was complete in 15 children with no recurrence during a mean follow-up of 5.25 years and incomplete in 3 requiring a second surgery. CONCLUSION: Surgery of SEGA represents a very effective treatment with low morbidity and no mortality in the present series. In patients operated before the onset of clinical signs of hydrocephalus, internal VPS could be avoided whereas in others, an additional shunt surgery became necessary. This gives arguments in favor of a regular MRI surveillance in tuberous sclerosis complex patients with SEGA in order to best propose resective surgery once a growth of tumor and/or ventricular size have been confirmed but before raised intracranial pressure occurs.

Refractory spasms of focal onset-A potentially curable disease that should lead to rapid surgical evaluation.

PURPOSE: Infantile spasms (IS) can occur as the only seizure type in children with surgically amenable epilepsies. Although early surgery has shown positive effects, little is known regarding outcomes. METHODS: We retrospectively reviewed all children with IS referred to our tertiary center between 2002 and 2014 and try to define factors of outcome. RESULTS: Sixty-eight children with focal onset seizures were referred: twenty children with a hemispheric implication and 48 with one or more lobes involved. The age of onset was significantly earlier in the hemispheric population (8.0 versus 16.7 months in the focal population). There was no difference in the age of onset between anterior and posterior onset zones, as we could expect regarding the maturation gradient. The epilepsy began earlier in life in tuberous sclerosis than in DNET. Only three children of the 48 non-hemispheric patients had a normal MRI at the time of the surgery. Temporal lobe was involved only in a third of the population. More than 86% of the patients were operated on. Patients with hemispheric lesions were operated on younger (2.6 years+/- 2.1 years) compared to 4.6+/- 3.5 years in the whole population. The most frequent etiologies were in descending order: dysplasia, ganglioglioma or dysembryoplastic tumours and tuberous sclerosis. The global seizure outcome was favorable (Engel 1a) in 74.6% of the patients, and 87.9% if the delay between the first seizure and the surgery was less than 36 months. It fell to 64.7% if the delay exceeded 50 months. CONCLUSION: Spasms of focal onset have a similar postsurgical outcome as other seizure types so surgery may be an excellent option for treating selected patients with focal infantile spasms. Volume and type but not topography of the lesion influence the age of onset. MRI is very helpful to locate the pathology in the pediatric population, since only a small portion had a normal MRI.

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.

Stereo-electroencephalography (SEEG) in children surgically cured of their epilepsy.

PURPOSE: SEEG in children has a low morbidity and leads to a good surgical outcome, in particular in younger patients. We analysed, in detail, the SEEG data of patients that were subsequently cured by surgery. METHODS: We selected the 48 children explored between 2009 and 2013 in our centre and surgically cured after SEEG-based resections with at least one-year follow-up. We retrospectively studied demographic and surgical data and paid particular attention to the data acquired during the invasive recording. Moreover, we compared the children younger than 5 years of age (group 1: 17 children) to those older than 5 years of age at the time of exploration (group 2: 31 patients). RESULTS: SEEG was well tolerated. Only one patient had slight intracerebral bleeding seen on the post-operative CT-scan without any clinical consequence and which did not prevent the recording. SEEG explored at least four lobes in 59% of patients, either because of a suspected very widespread epileptogenic zone or because of the lack of a precise hypothesis. Auras were recorded only in group 2 (32% of patients, P=0.0009). Despite these difficulties, SEEG led to tailored resections including multilobar resections in 14% and infralobar resections in 69% of patients. The electrical pattern of seizures had no particularities as compared with adults. Interictal spikes and slow waves outside the resection zone were significantly less frequent in group 1 (P=0.02). In symptomatic epilepsies, the lesion matched the irritative zone in only 11% of patients and the ictal onset zone in 32% respectively. CONCLUSION: Our study confirms the low morbidity of SEEG in children. SEEG can disclose a limited epileptogenic zone. Our data suggest that the epileptic network is less complex in younger patients, which has to be confirmed by a quantitative analysis of SEEG signals.

Hemispherotomy for isolated infantile spasms following perinatal ischemic stroke.

BACKGROUND: Infantile spasms (IS) are a severe epileptic encephalopathy. In patients with early focal ischemia and refractory IS, a preoperative evaluation is required even if IS are the only ictal manifestation. METHODS: We report three such patients who presented with IS between 5 and 7 months of age without any other focal seizure types. Imaging exhibited a perinatal middle cerebral artery (MCA) stroke. RESULTS: All patients had hemiparesis and experienced psychomotor regression after the onset of IS. Scalp video-electroencephalogram (EEG) monitoring for presurgical assessment showed interictal and ictal EEG characteristics between the pathological and the healthy hemisphere and surgery was proposed despite the lack of any focal seizures. The three patients underwent hemispherotomy at a mean age of 27 months and became seizure-free without medication (follow-up 49-144 months). The two patients who underwent early hemispherotomy acquired normal verbal intelligence, whereas the third, operated on at 38 months of age, remained with severe mental retardation. CONCLUSION: Early hemispherotomy in drug-resistant epilepsy related to a perinatal MCA may cure the seizures even if the patient has IS as sole type and prevent mental retardation in some children.