We identified in two awake surgery cases a postoperative double dissociation between phonological and graphemic output buffer deficits. Using lesion-symptom mapping from ischaemic mini-strokes and preoperative tractography, we demonstrated that the phonological (resp. graphemic) disorder fitted with ventral (resp. dorsal) damage to the AF. Further studies are needed to confirm our hypothesis of a ventro-dorsal functional organization within the AF for phonological versus graphemic processing.

Introduction Selective amygdalo-hippocampectomy (SAH) is commonly performed in drug-resistant mesial temporal lobe epilepsy (MTLE) with seizure-free outcome in 70-80% of patients, however cognitive risks with respect to surgical approaches remain debated. Research question The preliminary experience of a new surgical route through the orbit are evaluated with the aim to improve the benefits/risks of SAH. Methods Patients were recruited among a cohort of 100 patients investigated in the Epilepsy Unit of the department of Neurosurgery, between 2022 and 2024. A SAH through a transorbital approach with an eyebrow incision was performed in 3 patients (2 males, 22-51 years) after investigation for pure MTLE (right side in 2, non-lesional in 1).Surgical outcome was assessed with respect to seizures according to the International League Against Epilepsy (ILAE) classification. Results No local or general complications occurred postoperatively except a transient diplopia due to ocular oedema. Mean volume of resection was of 9.2 cc, and virtual dissection of tractograms demonstrated that the resection cavity spared the optic, uncinate and inferior longitudinal pathways in all cases.With a 12 to 31 month-follow-up (mean 22 months), seizure-free outcome (ILAE class 1) was obtained in all patients. Neuropsychological evaluation showed increased or stable cognitive and memory performances, with an improvement of quality of life (QOL) in all. Aesthetical results were excellent. Conclusion Transorbital eyebrow approach is safe and effective for SAH, with a positive impact on cognitive functions and QOL. Although preliminary, these findings suggest that it may be an option in patients with pure MTLE.

The neuronal K/Cl cotransporter KCC2 regulates the transmembrane chloride gradient, which controls the efficacy of GABAergic signaling. In mesial temporal lobe epilepsy (mTLE) and other neurological disorders, reduced KCC2 expression or function can result in depolarizing GABA signaling, which is thought to contribute to pathological activity and seizures. Therefore, restoring chloride homeostasis represents a promising therapeutic strategy. We investigated the mechanisms and antiseizure effects of two small molecules, prochlorperazine (PCPZ) and CLP- 257, that have been identified as potential KCC2 enhancers. We found that both compounds enhance KCC2 function and clustering in cortical neurons while reducing its membrane diffusion, without altering canonical regulatory phosphorylation. CLP- 257 also selectively increased extrasynaptic, but not synaptic, GABAA receptor- mediated currents. Using in vitro recordings from resected brain tissue of patients with drug- resistant mTLE and in vivo recordings from a mouse model, we show that PCPZ and CLP- 257 (or its prodrug CLP- 290) effectively suppressed spontaneous epileptiform activity in both models. These findings reveal that PCPZ and CLP- 257 act as genuine KCC2 enhancers and provide experimental evidence of the therapeutic potential of such compounds for treating drug- resistant mTLE.

Brain metastasis are the most frequent central nervous system tumors that usually occur during systemic malignancy. However, they can be diagnosed before the primary cancer site. The number of brain and systemic metastases and the identification of the primary cancer can favor specific treatments and impacts survival estimates. During surgery, intraoperative identification of metastatic tissue may help the surgical strategy and postoperative adjuvant treatment. The study of endogenous fluorescence of the brain tissue has already demonstrated its capability to differentiate metastasis tissue from control and identify specific optical signatures. In this study, based on deep ultraviolet and near-infrared excitation, we investigated for the first time the potentiality of the endogenous fluorescence analysis to characterize brain metastasis origin and to highlight the heterogeneity of molecular components and properties according to the metastasis sub-types, This study gives thus a glimpse of the possibility to find the primary cancer site from the secondary tumor.

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 β-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.

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

The neuronal K/Cl cotransporter KCC2 controls intraneuronal chloride and subsequently the efficiency of GABA signaling. In many neurological disorders, including mesial temporal lobe epilepsy (mTLE), reduced KCC2 expression or function may lead to depolarizing GABA signaling, which may then contribute to pathological activity and seizures. Compensating for the dysregulation of chloride transport in the pathology therefore appears to be a promising therapeutic strategy. Two small molecules - prochlorperazine (PCPZ) and CLP-257 - recently identified from library screening as candidate KCC2 enhancers, appear to improve symptoms in animal models of disorders associated with KCC2 extinction. However, their mode of action in cortical neurons and their therapeutic potential in epilepsy remain elusive and even controversial. Here, we show in rat hippocampal neurons that PCPZ and CLP-257 act by increasing KCC2 function and clustering while decreasing its membrane diffusion, independent of phosphorylation of canonical regulatory residues. Consistently, both compounds suppress spontaneous interictal-like discharges in postoperative tissue from patients with mTLE. Chronic administration of PCPZ also reduces seizure frequency and interictal activity in a mouse model of mTLE. These results unravel the mechanism of action of two KCC2 enhancers and validate their therapeutic potential in mesial temporal lobe epilepsy.

Objective: To describe pure insular ictal semiology and patterns of extra-insular spread demonstrated by stereoelectroencephalography (SEEG) according to a classification based on the insular cytoarchitecture. Methods: We investigated the ictal semiology in 17 patients undergoing SEEG for insular epilepsy. The insular cortex was divided into three regions roughly overlapping with the agranular, dysgranular and granular regions. Ictal semiology was described accordingly: anterior insula (AI, short anterior and middle gyri), middle insula (MI, short posterior and long anterior gyri) and posterior insula (PI, long posterior gyrus). Results: Awareness impairment occurred secondarily to extra-insular ictal spread. Subjective manifestations were constant. AI seizures (n = 3) presented with autonomic (increased heart rate [HR], respiratory changes), oropharyngeal (mainly throat sensations), emotional (fear, anguish) semiology and the "handto-throat" sign followed by frontal-like semiology. MI seizures (n = 8) presented with mainly non-painful paresthesia, some autonomic (respiratory, increased HR), oropharyngeal or thermic symptoms and early motor features with spread to the opercular cortex. PI seizures (n = 6) were characterized by somatosensory semiology, mainly paresthesia potentially painful, and cephalic sensations. Conclusions: Cytoarchitectonic-based classification and the corresponding ictal features support the antero-posterior grading of insular seizures and highlight specific ictal symptoms. Significance: This refinement of insular semiology can help optimize the planning of SEEG for presumed insular epilepsy. CO 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Nowadays, the ability to diagnose brain tumors intraoperatively and delineate their margins, as accurately as possible, is of primordial importance during surgery. However, the exact tumor boundaries and targets are difficult to find due to the similar visual appearances especially at the margins, leading in many cases to poor surgical outcomes and a high risk of recurrences. To solve this dogma, our group tried to determine different tissue optical signatures such as optical parameters and endogenous fluorescence. For that, we conducted a comparative study to differentiate between healthy and tumorous tissues under one- and two-photon excitations on optical properties to explore several optical parameters. In addition, the study of endogenous fluorescence can successfully help with the discrimination between tissue types using one- and two-photon excitations. This works suggests that the multimodal analysis of optical signatures of tissues could be a reliable technique that can be used to differentiate between healthy and tumorous tissues. This can help in the future with the implementation of such techniques in vivo during surgery to help the surgeon with the decision that needs to be taken as for tissue resection.

Introduction: Fibred-based optical spectroscopy is advantageous over imaging due to its sensitivity, practicality and precision, providing point of care diagnosis. The unique advantage is that the sampled volume is well defined by the source-detector geometry and that the functionality of multiple optical techniques can be incorporated into one probe so that more information is gained without extra bulkiness or cost, while also mitigating the limitations of each. Methods: This advantage is utilized here to address the limited accuracy in delineating brain tumors, in situ, by simultaneously characterizing tissue based on the spectral and lifetime properties of five endogenous fluorophores commonly present in brain tissue. A 5-meters multi fibre-optic probe custom-built for neurosurgery guidance with a sterilizable distal end is presented in this paper. It describes its technical features such as architecture, collection efficiency, sensitivity. Results and discussion: The developed probe have a temporal resolution of 34.6 ps and a temporal impulse response function of 29 ps. The spatial resolution was around 153 μm while the spectral resolution is 1 nm. All of these specifications are ensured under 1 second as acquisition time. The probe is validated using fluorescent dyes and tissue phantoms. Additionally, the fluorescence spectra from fresh and frozen animal tissue and from an epileptic patient are compared to that obtained from confocal fluorescence microscopy, while the lifetime values are compared to that reported in literature. Finally, the effect of pressure applied to the probe in contact with tissue is discussed.

Nowadays, surgical removal remains the standard method to treat brain tumors. During surgery, the neurosurgeon may encounter difficulties to delimitate tumor boundaries and the infiltrating areas as they have a similar visual appearance to adjacent healthy zones. These infiltrating residuals increase the tumor recurrence risk, which decreases the patient's post-operation survival time. To help neurosurgeons improve the surgical act by accurately delimitating healthy from cancerous areas, our team is developing an intraoperative multimodal imaging tool. It consists of a two-photon fluorescence fibered endomicroscope that is intended to provide a fast, real-time, and reliable diagnosis information. In parallel to the instrumental development, a large optical database is currently under construction in order to characterize healthy and tumor brain tissues with their specific optical signature using multimodal analysis of the endogenous fluorescence. Our previous works show that this multimodal analysis could provide a reliable discrimination response between different tissue types based on several optical indicators. Here, our goal is to show that the two-photon fibered endomicroscope is able to provide, based on the same approved indicators in the tissue database, the same reliable response that could be used intraoperatively. We compared the spectrally resolved and time-resolved fluorescence signal, generated by our two-photon bimodal endoscope from 46 fresh brain tissue samples, with a similar signal provided by a standard reference benchtop multiphoton microscope that has been validated for tissue diagnosis. The higher excitation efficiency and collection ability of an endogenous fluorescence signal were shown for the endoscope setup. Similar molecular ratios and fluorescence lifetime distributions were extracted from the two compared setups. Spectral discrimination ability of the bimodal endoscope was validated. As a preliminary step before tackling multimodality, the ability of the developed bimodal fibered endoscope to excite and to collect efficiently as well as to provide a fast exploitable high-quality signal that is reliable to discriminate different types of human brain tissues was validated.

•The transorbital approach combining eyebrow incision and crescent-shaped craniotomy increases the surgical freedom to access the anterior and middle skull-base.•The technic allows the use of both endoscope and microscope.•The concept is at the crossroad between the supraorbital keyhole and endoscopic trans-orbital approach.

Delineating brain tumor margins as accurately as possible is a challenge faced by the neurosurgeon during tumor resections. The extent of resection is correlated with the survival rate of the patient while preserving healthy surrounding tissues is necessary. Real-time analysis of the endogenous fluorescence signal of brain tissues is a promising technique to answer this problem. Multimodal optical analysis has been proved to be a powerful tool to discriminate tumor samples of different grade of gliomas and meningiomas from healthy control samples. In this study, Machine Learning methods are evaluated to improve the accuracy of such discrimination. Each sample is described by 16 feature given in input to a Decision Tree based model. Once the learning step is completed, the classifier achieves a 95% correct classification on unknown samples. This study shows the potential of Machine Learning to discriminate between tumoral and non tumoral tissues based on optical parameters.

Meningioma is the most common primary intracranial extra-axial tumor. Total surgical removal is the standard therapeutic method to treat this type of brain tumors. However, the risk of recurrence depends on the tumor grade and the extent of the resection including the infiltrated dura mater and, if necessary, the infiltrated bone. Therefore, proper resection of all invasive tumor borders without touching eloquent areas is of primordial in order to decrease the risk of recurrence. Nowadays, none of the intraoperative used tools is able to provide a precise real-time histopathological information on the tumor surrounding areas to help the surgeon to achieve a gross total removal. To respond to this problem, our team is developing a multimodal two-photon fluorescence endomicroscope, compatible with the surgeon tool, to better delimitate tumor boundaries, relying on the endogenous fluorescence of brain tissues. In this context, we are building a tissue database in order to specify each brain tissue, whether healthy or tumoral, with its specific optical signature. In this study, we present a multimodal and multiscale optical measurements on non-tumoral control brain tissue obtained in epilepsy surgery patients and several meningioma grades. We investigated tissue auto-fluorescence to track the molecular changes associated with the tumor grade from deep ultra-violet (DUV) to near infrared (NIR) excitation. Micro-spectroscopy, fluorescence lifetime imaging, two-photon fluorescence imaging and Second Harmonic Generation (SHG) imaging were performed. Several optically derived parameters such as collagen crosslinks fluorescence in DUV, SHG emission in NIR and long lifetime intensity fraction of Nicotinamide Adenine Dinucleotide and Flavins were correlated to discriminate cancerous tissue from control one. While collagen response managed to discriminate meningioma grades from control samples with a 100% sensitivity and 90% specificity through a 3D discriminative algorithm.

BACKGROUND: Multiple biopsy samples are warranted for the histomolecular diagnosis of diffuse gliomas in the current molecular era, which possibly increases morbidity. OBJECTIVE: We assessed diagnostic yield, safety, and risk factors of postoperative morbidity after robot-assisted serial stereotactic biopsy sampling along 1 biopsy trajectory for diffuse gliomas. METHODS: Observational retrospective analysis of consecutive magnetic resonance imagingebased robotassisted stereotactic biopsies performed at a single institution to assess the diagnosis of nonresectable newly diagnosed supratentorial diffuse gliomas in adults (2006-2016). RESULTS: In 377 patients, 4.2 +/- 1.9 biopsy samples were obtained at 2.6 +/- 1.2 biopsy sites. The histopathologic diagnosis was obtained in 98.7% of cases. Preoperative neurologic deficit (P = 0.030), biopsy site hemorrhage >= 20 mm (P = 0.004), and increased mass effect on postoperative imaging (P = 0.014) were predictors of a new postoperative neurologic deficit (7.7%). Postoperative neurologic deficit (P < 0.001) and increased mass effect on postoperative imaging (P = 0.014) were predictors of a Karnofsky Performance Status decrease >= 20 points postoperatively (4.0%). Increased intracranial pressure preoperatively (P = 0.048) and volume of the contrast-enhanced area >= 13 cm(3) (P = 0.048) were predictors of an increased mass effect on postoperative imaging (4.4%). Preoperative Karnofsky Performance Status <70 (P = 0.045) and increased mass effect on postoperative imaging (P < 0.001) were predictors of mortality 1 month postoperatively (2.9%). Preoperative neurologic deficit (P = 0.005), preoperative Karnofsky Performance Status <70 (P < 0.001), subventricular zone contact (P = 0.004), contrast enhancement (P = 0.018), and steroid use (P = 0.003), were predictors of the inability to discharge to home postoperatively (37.0%). CONCLUSIONS: Robot-assisted stereotactic biopsy sampling results in high diagnostic accuracy with low complication rates. Multiple biopsy sites and samples do not increase postoperative complications.

BACKGROUND:Postoperative intracerebral haematomas represent a serious complication following stereotactic biopsy. We investigated the possible underlying causes - poor planning or poor execution - of postoperative intracerebral haematomas following stereotactic biopsies.METHODS:We performed a technical investigation using a retrospective single-centre consecutive series of robot-assisted stereotactic biopsies for a supratentorial diffuse glioma in adults. Each actual biopsy trajectory was reviewed to search for a conflict with an anatomical structure at risk.RESULTS:From 379 patients, 12 (3.2%) presented with a postoperative intracerebral haematoma ≥20 mm on postoperative CT-scan (3 requiring surgical evacuation); 11 of them had available intraoperative imaging (bi-planar stereoscopic teleangiography x-rays at each biopsy site). The actual biopsy trajectory was similar to the planned biopsy trajectory in these 11 cases. In 72.7% (8/11) of these cases, the actual biopsy trajectory was found to contact a structure at risk (blood vessel and cerebral sulcus) and identified as the intracerebral haematoma origin.CONCLUSIONS:Robot-assisted stereotactic biopsy is an accurate procedure. Postoperative intracerebral haematomas mainly derive from human-related errors during trajectory planning.