Deep retroinsular and parieto-opercular origin of vestibular symptoms: A stereoelectrocenphalography (SEEG) study.

Several studies have shown that the retroinsular and posterior parietal operculum regions play a central role in vestibular processing. Electrical stimulations performed during stereoelectroencephalography (SEEG) in patients with focal drug-resistant epilepsy could contribute to the analysis of this area. Among the 264 SEEGs performed in both an adult and a paediatric epilepsy surgery centre, we retrospectively identified 24 patients (9%) reporting vertigo during electrical stimulations (ES). In seven of them (29% of patients experiencing vertigo during ES), it was evoked by stimulating the retroinsular region. The reported responses were mostly not rotatory sensations but actually illusions of body, limb or limb segment movement. The involved area is limited. Moreover, two patients reported having the same symptoms at the beginning of their seizures starting in the same region. Our case study confirms the pivotal role of the retroinsular and posterior parietal operculum areas in vestibular responses, and we therefore advise the exploration of this region when patients report an illusion of body movement at the beginning of their seizures.

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.

Preservation of frontal white matter tracts in ventricular surgery: favoring an anterior interhemispheric transcallosal approach vs a transcortical transfrontal transventricular approach.

Secondary to the creation of a surgical corridor and retraction, white matter tracts degenerate, causing long-term scarring with potential neurological consequences. Third and lateral ventricle tumors require surgery that may lead to cognitive impairment. Our objective is to compare the long-term consequences of a transcortical transfrontal approach and an interhemispheric transcallosal approach on corpus callosum and frontal white matter tracts degeneration. Surgical patients with ventricular tumor accessible through both approaches were included and clinico-radiological data were retrospectively analyzed. The primary endpoint was the callosotomy length at 3-month post-operative T1 MRI, corrected by the extension of the tumor and the use of neuronavigation. Secondary outcomes included perioperative criteria such as bleeding, use of retractors and duration, FLAIR hypersignal on 3-month MRI, and re-do surgeries. To assess white matter tract interruption, 3-month FLAIR hypersignal was superposed to a tractography atlas. Seventy patients were included, 57 (81%) in the transfrontal group and 13 (19%) in the interhemispheric group. There was no difference in the mean callosotomy length on 3-month MRI (12.3 mm ± 5.60 transfrontal vs 11.7 mm ± 3.92 interhemispheric, p = 0.79) on univariate and multivariate analyses. The callosotomy length was inferior by - 3.13 mm for tumors located exclusively in the third ventricle (p = 0.016), independent of the approach. Retractors were used more often in transfrontal approaches (60% vs 33%, p < 0.001). The extent of frontal FLAIR hypersignal was higher after transfrontal approach (14.1 mm vs 0.525 mm, p < 0.001), correlated to the use of retractors (p < 0.05). After the interhemispheric approach, no tract other than corpus callosum was interrupted, whereas, after the transfrontal approach, frontal arcuate fibers and projections from the thalamus were interrupted in all patients, the cingulum in 19 (33%), the superior fronto-occipital fasciculus in 15 (26%), and the superior longitudinal fasciculus in 2 (3%). Transfrontal and interhemispheric approaches to the third and lateral ventricles both lead to the same long-term damage to the corpus callosum, but the transfrontal approach interrupts several white matter tracts essential to cognitive tasks such as attention and planning, even in the non-dominant hemisphere. These results encourage all neurosurgeons to be familiar with both approaches and favor the interhemispheric approach when both can give access to the tumor with a comparable risk. Neuropsychological studies are necessary to correlate these anatomical findings to cognitive outcomes.

Vertical parasagittal hemispherotomy: a case report of postoperative mesio-temporal seizures via amygdalofugal pathway.

Vertical parasagittal hemispherotomy (VPH) is a well-established surgical treatment which is proposed for children with widespread unilateral onset of intractable epileptic seizures. VPH allows to disconnect from a vertical transventricular approach all white matter fibers of the hemisphere around a central core including the thalamus. We present the case of a girl who underwent VPH for hemimegalencephaly in early infancy. Postoperatively, she developed unexpected seizures of mesio-temporal origin. Stereo-EEG provided arguments for an amygdalar origin. High-resolution MRI with tractography confirmed the presence of the amygdalo-fugal pathway to be responsible of epileptic discharges propagation. She became seizure-free after temporal resection.

The landscape of epilepsy-related GATOR1 variants.

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Correction to: The landscape of epilepsy-related GATOR1 variants.

The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.

Correction: The landscape of epilepsy-related GATOR1 variants.

The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.

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.

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.

[A unusual brain cortical tumor: angiocentric glioma]. / Une tumeur cérébrale corticale peu commune : le gliome angiocentrique.

We report the case of an 11-year-old girl, who was admitted for surgery of an epilepsy-associated brain tumor. The radiological and clinical hypothesis was dysembryoplasic neuroepithelial tumor. Histopathological examination revealed a tumoral proliferation composed of spindle-shaped cells with palisade arrangements around vessels. Tumor cells have small, round and regular nuclei without atypia or mitosis. On immunohistochemistry, the neoplastic cells strongly expressed GFAP and showed a characteristic cytoplasmic dot-like staining with EMA (epithelial membrane antigen). Ki-67 labeling index was low. Molecular analysis failed to reveal the V600E mutation of BRAF gene. The patient was free of seizures after surgery. Angiocentric glioma is a rare brain tumor occuring preferably in children and young adults and is associated with seizures. The precise histogenesis remains debated. The treatment of choice is total resection. The prognosis is favorable if totally resected.

Stereo-electroencephalography (SEEG) in 65 children: an effective and safe diagnostic method for pre-surgical diagnosis, independent of age.

AIM: We report our experience of stereoelectroencephalography (SEEG) in 65 children with drug-resistant seizures, with a particular emphasis on young children. METHODS: We retrospectively studied all SEEG performed between 2009 and 2011 in our centre. As SEEG can have several indications, the patients were classified into three categories, according to the probability of surgery. The contribution of SEEG to the final decision regarding surgery was evaluated for each category separately. We also compared the main demographic and surgical data of children younger than 5 years of age (Group 1; 21 children) with those older than five years of age at the time of investigation (Group 2; 44 patients). RESULTS: MRI was not contributory in 20% of patients (9.5% in group 1; 25% in group 2). Electrical stimulations localised the motor area in all patients when performed (49% of patients), even in group 1 (62% of patients). SEEG led to surgery in 78% of patients (90.5% in group 1; 73% in group 2), after a second invasive investigation in 9.2 % of patients. The resection involved more than one lobe in 25% of patients (37% in group 1; 19% in group 2). Ultimately, 78% of patients with a low probability of having surgery before SEEG received surgery (88% in group 1). The surgical outcome of Engel class 1 was reported for 67% of patients (79% of patients in group 1 and 59% in group 2). No complications occurred. CONCLUSION: SEEG in children is safe and useful, and the surgical outcome in younger children is as good as, or sometimes even better than, that in older children. As a result of lower rates of complication and morbidity, SEEG appears to be more appropriate, in comparison to subdural grids, in situations where it is unclear if patients will have surgery after an invasive investigation.

Insights on cognitive reorganization after hemispherectomy in Rasmussen's encephalitis. A narrative review.

Rasmussen's encephalitis is a rare neurological pathology affecting one cerebral hemisphere, therefore, posing unique challenges. Patients may undergo hemispherectomy, a surgical procedure after which cognitive development occurs in the isolated contralateral hemisphere. This rare situation provides an excellent opportunity to evaluate brain plasticity and cognitive recovery at a hemispheric level. This literature review synthesizes the existing body of research on cognitive recovery following hemispherectomy in Rasmussen patients, considering cognitive domains and modulatory factors that influence cognitive outcomes. While language function has traditionally been the focus of postoperative assessments, there is a growing acknowledgment of the need to broaden the scope of language investigation in interaction with other cognitive domains and to consider cognitive scaffolding in development and recovery. By synthesizing findings reported in the literature, we delineate how language functions may find support from the right hemisphere after left hemispherectomy, but also how, beyond language, global cognitive functioning is affected. We highlight the critical influence of several factors on postoperative cognitive outcomes, including the timing of hemispherectomy and the baseline preoperative cognitive status, pointing to early surgical intervention as predictive of better cognitive outcomes. However, further specific studies are needed to confirm this correlation. This review aims to emphasize a better understanding of mechanisms underlying hemispheric specialization and plasticity in humans, which are particularly important for both clinical and research advancements. This narrative review underscores the need for an integrative approach based on cognitive scaffolding to provide a comprehensive understanding of mechanisms underlying the reorganization in Rasmussen patients after hemispherectomy.

Stereoelectroencephalography-guided radiofrequency thermocoagulation.

Within the neurosurgeon's armamentarium, stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) is an elegant tool to manage epilepsy in selected cases. This technique can 1) be curative when targeting small-volume ictal onset zones, 2) be used as a diagnostic tool by observing the consequences of coagulation on seizures or by recording the epileptic network in SEEG, and 3) offer palliative treatment through multiple lesions within a wide epileptic network. It is performed on awake patients, under continuous neurological evaluation, while monitoring impedance, time, and energy delivered. It could offer highly favorable outcomes in some cases, as in periventricular nodular heterotopia where 81% of patients are responders.

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.

Genetic Insights Into Hypothalamic Hamartoma: Unraveling Somatic Variants.

Objectives: Hypothalamic hamartomas (HHs) are rare developmental brain lesions associated with drug-resistant epilepsy and often subjected to epilepsy surgery. Brain somatic variants in genes affecting the Sonic hedgehog (Shh) and primary cilia signaling pathways have been implicated in approximately 50% of nonsyndromic HH cases. This study aims to characterize a new cohort of 9 HH cases and elucidate their genetic etiology. Methods: We recruited 9 HH cases including 8 nonsyndromic cases of which 4 were type IV HH. Genomic DNA was extracted from peripheral blood and surgical brain tissues, and somatic variants were investigated using high-depth whole-exome sequencing. Results: Pathogenic somatic variants in known HH genes (GLI3, OFD1, and PRKACA) were identified in 7 of the 9 cases. In addition, a 2-hit mutational event comprising a germline variant (predicted to impair kinase activity) and a somatic loss-of-heterozygosity was identified in TNK2, a gene encoding a brain-expressed tyrosine kinase. Discussion: Our findings reinforce the role of somatic variants in Shh and cilia genes in HH cases while also shedding light on TNK2 as a potential novel disease-causing gene. This study emphasizes the increasing importance of brain mosaicism in epilepsy disorders and underscores the critical role of genetic diagnosis derived from resected brain tissue.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Detection of brain somatic mutations in focal cortical dysplasia during epilepsy presurgical workup.

Brain-restricted somatic variants in genes of the mechanistic target of rapamycin signalling pathway cause focal epilepsies associated with focal cortical dysplasia type II. We hypothesized that somatic variants could be identified from trace tissue adherent to explanted stereoelectroencephalography electrodes used in the presurgical epilepsy workup to localize the epileptogenic zone. We investigated three paediatric patients with drug-resistant focal epilepsy subjected to neurosurgery. In the resected brain tissue, we identified low-level mosaic somatic mutations in AKT3 and DEPDC5 genes. We collected stereoelectroencephalography depth electrodes in the context of a second presurgical evaluation and identified 4/33 mutation-positive electrodes that were either located in the epileptogenic zone or at the border of the dysplasia. We provide the proof-of-concept that somatic mutations with low levels of mosaicism can be detected from individual stereoelectroencephalography electrodes and support a link between the mutation load and the epileptic activity. Our findings emphasize future opportunities for integrating genetic testing from stereoelectroencephalography electrodes into the presurgical evaluation of refractory epilepsy patients with focal cortical dysplasia type II to improve the patients' diagnostic journey and guide towards precision medicine.

Complete callosotomy in children with drop attacks; A retrospective monocentric study of 50 patients.

PURPOSE: Corpus callosotomy is a palliative surgical procedure for patients with drug-resistant epilepsy and suffering from drop attacks, which are a source of major deterioration in quality of life and can be responsible for severe traumatic injury. The objective of this study is to identify clinical markers that would predict a better outcome in terms of drop attacks and other types of epileptic seizures. METHODS: We reviewed a retrospective series of children who underwent complete corpus callosotomy at our institution, between January 1998 and February 2019. We analyzed the neurological and cognitive pre- and postoperative status, radiological datas, and electroencephalography (EEG) monitoring data. RESULTS: Fifty children underwent a complete callosotomy at a mean age of 7.5 years. The median postoperative follow-up was 42.5 months. Forty-one patients (82%) had a favorable outcome, 29 (58%) of them becoming totally free of drop attacks. Statistical analysis of correlation between outcome of drop attacks and the characteristics of the patients did not find any trend in terms of age, etiology or developmental level. Regarding seizure types, the probability of being drop attack-free was significantly higher in case of tonic seizures (p = 0.017). Neurological complications occurred in two patients. A transient disconnection syndrome was observed in one child with good preoperative cognitive level. The mean hospital stay was short (5 -10 days). CONCLUSION: The results of this large monocentric case series with a long follow-up indicate that total callosotomy is a safe and effective treatment for children with drug-resistant epileptic drop attacks. Aside from a better surgical outcome for children with tonic seizures causing the falls, the lack of any other significant prognostic factor implies that no patient should a priori be excluded from this palliative surgical indication.