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The trafficking of autoreactive leucocytes across the blood–brain barrier endothelium is a hallmark of multiple sclerosis pathogenesis. Although the blood–brain barrier endothelium represents one of the main CNS borders to interact with the infiltrating leucocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis. In addition, MCAM was preferentially upregulated on blood–brain barrier endothelial cells in multiple sclerosis lesions in situ and at experimental autoimmune encephalomyelitis disease onset by molecular MRI. In vitro and in vivo, we demonstrate that MCAM on blood–brain barrier endothelial cells contributes to experimental autoimmune encephalomyelitis development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the blood–brain barrier. Last, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the blood–brain barrier in vitro, in vivo and in multiple sclerosis lesions as detected by flow cytometry on rapid autopsy derived brain tissue from multiple sclerosis patients. Collectively, our findings reveal that MCAM is at the centre of a pathological pathway used by brain endothelial cells to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat multiple sclerosis.

Abstract. According to previous research, the insula is important for processing salient and emotional stimuli, but its precise role remains elusive. By combining high spatial and temporal resolution, intracranial electroencephalography (iEEG) might contribute to filling this gap. Four drug-resistant epileptic patients with intracranial electrodes in the insula were instructed to watch and rate pictures with sexual content and neutral pictures. Event-related potentials (ERPs) were computed separately for both types of stimuli. Ninety-three percent of the anterior insula (AI) and 85% of the posterior insula (PI) contacts showed differences between ERPs. AI-positive deflections tended to have an earlier onset than PI-positive deflections. The results suggest that the AI generates a P300-like response and contributes to the early phase of the late positive potential, both components found enhanced while viewing emotional stimuli in the ERP literature. The present findings are interpreted as congruent with the role of the AI in maintaining attention to salient stimuli.

Déjà-vu is a mental phenomenon commonly experienced during temporal lobe seizures and can be evoked by electrical stimulation of the temporal lobe. We analyzed reproducible déjà-vu experiences evoked by stimulating the insula in two patients with pharmacoresistant temporal lobe epilepsy.We reviewed video-electroencephalography (EEG) recordings from extraoperative electrical cortical stimulation sessions. In addition, we performed the directed transfer function (DTF) effective connectivity measure of monopolar signals in Patient 1. To highlight elective changes due to each stimulation, we subtracted pre-stimulation DTF matrices from early poststimulation matrices. This analysis was performed for both non-inducing-déjàvu stimulation (control matrix) and déjà-vu-inducing stimulation (active matrix). Finally, the control matrix was subtracted from the active matrix.Comparison of effective connectivity during control stimulation versus déjà-vu-inducing stimulation revealed a reversal of connectivity levels in three main regions: the contralateral inferior insula (the ipsilateral insula could not be analyzed), bilateral mesiotemporal regions and the ipsilateral superior frontal gyrus. The drivers of evoked déjà-vu were the mesiotemporal regions (mainly ipsilateral) and the ipsilateral superior frontal gyrus.Although our findings are possibly anecdotal, the insula may (in rare instances) remotely generate unexpected déjà-vu. If confirmed by further studies, this might change the assessment strategy for possible causes of anterior temporal lobectomy failure.

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.

The Socialist Republic of Vietnam is a developing country with an estimated population of 96.2 million as of 2019. The prevalence rate of epilepsy is between 4.4 and 14 per 1000 population. The care of epileptic patients in Vietnam is suboptimal for many reasons: insufficient resources, poor infrastructure, lack of education (to both patients and physicians), and inadequate offer of medical and surgical treatment options for epilepsy.

OBJECTIVEOperculoinsular cortectomy (also termed operculoinsulectomy) is increasingly recognized as a therapeutic option for perisylvian refractory epilepsy. However, most neurosurgeons are reluctant to perform the technique because of previously experienced or feared neurological complications. The goal of this study was to quantify the incidence of basic neurological complications (loss of primary nonneuropsychological functions) associated with operculoinsular cortectomies for refractory epilepsy, and to identify factors predicting these complications.METHODSClinical, imaging, and surgical data of all patients investigated and surgically treated by our team for refractory epilepsy requiring an operculoinsular cortectomy were retrospectively reviewed. Patients with tumors and encephalitis were excluded. Logistic regression analysis was used for uni- and multivariate statistical analyses.RESULTSForty-four operculoinsular cortectomies were performed in 43 patients. Although postoperative neurological deficits were frequent (54.5% of procedures), only 3 procedures were associated with a permanent significant neurological deficit. Out of the 3 permanent deficits, only 1 (2.3%; a sensorimotor hemisyndrome) was related to the technique of operculoinsular cortectomy (injury to a middle cerebral artery branch), while the other 2 (arm hypoesthesia and hemianopia) were attributed to cortical resection beyond the operculoinsular area. With multivariate analysis, a postoperative neurological deficit was associated with preoperative insular hypometabolism on PET scan. Postoperative motor deficit (29.6% of procedures) was correlated with fewer years of neurosurgical experience and frontal operculectomies, but not with corona radiata ischemic lesions. Ischemic lesions in the posterior two-thirds of the corona radiata (40.9% of procedures) were associated with parietal operculectomies, but not with posterior insulectomies.CONCLUSIONSOperculoinsular cortectomy for refractory epilepsy is a relatively safe therapeutic option but temporary neurological deficits after surgery are frequent. This study highlights the role of frontal/parietal opercula resections in postoperative complications. Corona radiata ischemic lesions are not clearly related to motor deficits. There were no obvious permanent neurological consequences of losing a part of an epileptic insula, including on the dominant side for language. A low complication rate can be achieved if the following conditions are met: 1) microsurgical technique is applied to spare cortical branches of the middle cerebral artery; 2) the resection of an opercula is done only if the opercula is part of the epileptic focus; and 3) the neurosurgeon involved has proper training and experience.

OBJECTIVEPatients with refractory epilepsy of operculoinsular origin are often denied potentially effective surgical treatment with operculoinsular cortectomy (also termed operculoinsulectomy) because of feared complications and the paucity of surgical series with a significant number of cases documenting seizure control outcome. The goal of this study was to document seizure control outcome after operculoinsular cortectomy in a group of patients investigated and treated by an epilepsy team with 20 years of experience with this specific technique.METHODSClinical, imaging, surgical, and seizure control outcome data of all patients who underwent surgery for refractory epilepsy requiring an operculoinsular cortectomy were retrospectively reviewed. Tumors and progressive encephalitis cases were excluded. Descriptive and uni- and multivariate analyses were done to determine seizure control outcome and predictors.RESULTSForty-three patients with 44 operculoinsular cortectomies were studied. Kaplan-Meier estimates of complete seizure freedom (first seizure recurrence excluding auras) for years 0.5, 1, 2, and 5 were 70.2%, 70.2%, 65.0%, and 65.0%, respectively. With patients with more than 1 year of follow-up, seizure control outcome Engel class I was achieved in 76.9% (mean follow-up duration 5.8 years; range 1.25–20 years). With multivariate analysis, unfavorable seizure outcome predictors were frontal lobe–like seizure semiology, shorter duration of epilepsy, and the use of intracranial electrodes for invasive monitoring. Suspected causes of recurrent seizures were sparing of the language cortex part of the focus, subtotal resection of cortical dysplasia/polymicrogyria, bilateral epilepsy, and residual epileptic cortex with normal preoperative MRI studies (insula, frontal lobe, posterior parieto-temporal, orbitofrontal).CONCLUSIONSThe surgical treatment of operculoinsular refractory epilepsy is as effective as epilepsy surgeries in other brain areas. These patients should be referred to centers with appropriate experience. A frontal lobe–like seizure semiology should command more sampling with invasive monitoring. Recordings with intracranial electrodes are not always required if the noninvasive investigation is conclusive. The complete resection of the epileptic zone is crucial to achieve good seizure control outcome.

Background and ObjectivesIn multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor–like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS.MethodsExpression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP.ResultsUsing bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS.DiscussionCollectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.

The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (T

DICAM contributes to the pathogenesis of autoimmune neuroinflammation by promoting the migration of T H 17 lymphocytes across the blood-brain barrier.

Functional neuroimaging studies using auditory stimuli consistently show activation of the insular cortex. However, due to the limited temporal resolution of non-invasive neuroimaging techniques, the role(s) of the insula in auditory processing remains unclear. As the anterior insula (aI) and the posterior insula (pI) have different connections and are thought to be functionally distinct, it is likely that these two areas contribute differently to auditory processing. Our study examines the spatiotemporal dynamics of auditory processing in the insula using intracranial electroencephalography (EEG). Eight epileptic patients completed two passive listening tasks and one three-stimulus auditory oddball detection task during the intracranial EEG monitoring of their drug-resistant seizures. Recordings were obtained from depth electrodes implanted in 11 insulae. Event-related potentials (ERPs) were analyzed using permutation analyses during the N100 and the P300 intervals, and modulations of alpha, theta, and gamma band responses were compared using Wilcoxon/Mann-Whitney analyses. N100 responses to auditory stimuli were mostly observed in the pI and were little affected by task conditions. Auditory target detection was associated with P300 ERPs, and alpha, theta, high- and low-gamma responses, preferentially at aI contacts. Results suggest that the aI is involved in voluntary attentional processing of task-relevant information, whereas the pI is involved in automatic auditory processing.

Introducción: Los pacientes con convulsiones intratables que no son candidatos para la cirugía de resección focal están indicados para un procedimiento quirúrgico paliativo, la callosotomía. Este procedimiento se basa en la hipótesis de que el cuerpo calloso es una importante vía para la propagación interhemisférica de la actividad epiléptica y, para la epilepsia resistente a fármacos. Presenta relativamente baja morbilidad permanente y una eficacia en el control de las convulsiones. Sobre la base de la literatura, la callostomía mejora la calidad de vida de los pacientes que tiene la indicación para realizar este procedimiento, ya que permite reducir la frecuencia de las crisis, ya sean tónica o átona, tónico-clónicas, ausencia o lóbulo frontal crisis parciales complejas. Objetivo: El objetivo de esta revisión de la literatura es discutir los detalles técnicos, modalidades, riesgos, complicaciones, resultados y de pronóstico de callosotomía basado en la revisión crítica de la literatura y la experiencia de los autores. Casuística y Métodos: Se realizó la consulta bibliográfica, utilizando la base de datos MEDLINE, LILACS, SciELO, que utiliza el lenguaje como criterios de selección, la elección de los artículos recientes preferiblemente en portugués, español o Inglés, con el año de publicación superior a 2000. Conclusión: De acuerdo con la experiencia y las referencias del autor, callosotomía es un procedimiento seguro cuando indicado para casos seleccionados y la tasa de éxito es proporcional a la extensión de la resección del cuerpo calloso. A mayor resección puede reducir la frecuencia de las crisis, sin embargo, la morbilidad puede ser también mayor. No hay ningún estudio que compara la estimulación del nervio vago frente a frente callosotomía VNS más callososotomy, lo que sería la futura necesaria para una importante fuente de datos sobre este tema.

Background: We aimed to evaluate heart rate variability (HRV) changes in insulo-opercular epilepsy (IOE) and after insulo-opercular surgery. Methods: We analyzed 5-min resting HRV of IOE patients before and after surgery. Patients’ SUDEP-7 risk inventory scores were also calculated. Results were compared with age- and sex-matched patients with temporal lobe epilepsy (TLE) and healthy individuals. Results: There were no differences in HRV measurements between IOE, TLE, and healthy control groups (and within each IOE group and TLE group) in preoperative and postoperative periods. In IOE patients, the SUDEP-7 score was positively correlated with pNN50 (percentage of successive RR intervals that differ by more than 50 ms) (p = 0.008) and RMSSD (root mean square of successive RR interval differences) (p = 0.019). We stratified IOE patients into those whose preoperative RMSSD values were below (Group 1a = 7) versus above (Group 1b = 9) a cut-off threshold of 31 ms (median value of a healthy population from a previous study). In group 1a, all HRV values significantly increased after surgery. In group 1b, time-domain parameters significantly decreased postoperatively. Conclusions: Our results suggest that in IOE, HRV may be either decreased in parasympathetic tone or increased globally in both sympathetic and parasympathetic tones. We found no evidence that insulo-opercular surgeries lead to major autonomic dysfunction when a good seizure outcome is reached. The increase in parasympathetic tone observed preoperatively may be of clinical concern, as it was positively correlated with the SUDEP-7 score.

Interictal epileptiform discharges (IEDs) are brief neuronal discharges occurring between seizures in patients with epilepsy. The characterization of the hemodynamic response function (HRF) specific to IEDs could increase the accuracy of other functional imaging techniques to localize epileptiform activity, including functional near-infrared spectroscopy and functional magnetic resonance imaging. This study evaluated the possibility of using an intraoperative multispectral imaging system combined with electrocorticography (ECoG) to measure the average HRF associated with IEDs in eight patients. Inter-patient variability of the HRF is illustrated in terms of oxygenated hemoglobin peak latency, oxygenated hemoglobin increase/decrease following IEDs, and signal-to-noise ratio. A sub-region was identified using an unsupervised clustering algorithm in three patients that corresponded to the most active area identified by ECoG.

Operculo-insular epilepsy (OIE) is an under-recognized condition that can mimic temporal and extratemporal epilepsies. Previous studies have revealed structural connectivity changes in the epileptic network of focal epilepsy. However, most reports use the debated streamline-count to quantify ‘connectivity strength’ and rely on standard tracking algorithms. We propose a sophisticated cutting-edge method that is robust to crossing fibers, optimizes cortical coverage, and assigns an accurate microstructure-reflecting quantitative conectivity marker, namely the COMMIT (Convex Optimization Modeling for Microstructure Informed Tractography)-weight. Using our pipeline, we report the connectivity alterations in OIE. COMMIT-weighted matrices were created in all participants (nine patients with OIE, eight patients with temporal lobe epilepsy (TLE), and 22 healthy controls (HC)). In the OIE group, widespread increases in ‘connectivity strength’ were observed bilaterally. In OIE patients, ‘hyperconnections’ were observed between the insula and the pregenual cingulate gyrus (OIE group vs. HC group) and between insular subregions (OIE vs. TLE). Graph theoretic analyses revealed higher connectivity within insular subregions of OIE patients (OIE vs. TLE). We reveal, for the first time, the structural connectivity distribution in OIE. The observed pattern of connectivity in OIE likely reflects a diffuse epileptic network incorporating insular-connected regions and may represent a structural signature and diagnostic biomarker.

Background Operculoinsular cortectomy is increasingly recognized as a therapeutic avenue for perisylvian refractory epilepsy. However, most neurosurgeons are reluctant to perform this type of procedure because of feared neurological complications, especially in the language-dominant hemisphere, as the insula is involved in speech and language processes. The goal of this retrospective study is to quantify the incidence and types of speech and language deficits associated with operculoinsulectomies in the dominant hemisphere for language, and to identify factors associated with these complications. Methods Clinical, imaging, and surgical data of all patients who had an operculoinsulectomy for refractory epilepsy at our center between 1998 and 2018 were reviewed. Language lateralization was determined by functional magnetic resonance imaging (fMRI) and/or Wada test. Speech and language assessments were carried out by neurosurgeons, neurologists, neuropsychologists and/or speech language pathologists, before surgery, during the first week after surgery, and at least 6 months after surgery. Results Amongst 44 operculoinsulectomies, 13 were performed in the language-dominant hemisphere. 46% of these patients presented with transient aphasia post-surgery. However, a few months later, the patients’ performances on language assessments were not statistically different from before surgery, thus suggesting a complete recovery of speech and language functions. Conclusion Temporary aphasias after operculoinsulectomy for refractory epilepsy in the language-dominant hemisphere are frequent, but eventually subside. Potential mechanisms underlying this recovery are discussed.

Introduction: To date, clinical trials of deep brain stimulation (DBS) for refractory chronic pain have yielded unsatisfying results. Recent evidence suggests that the posterior insula may represent a promising DBS target for this indication. Methods: We present a narrative review highlighting the theoretical basis of posterior insula DBS in patients with chronic pain. Results: Neuroanatomical studies identified the posterior insula as an important cortical relay center for pain and interoception. Intracranial neuronal recordings showed that the earliest response to painful laser stimulation occurs in the posterior insula. The posterior insula is one of the only regions in the brain whose low-frequency electrical stimulation can elicit painful sensations. Most chronic pain syndromes, such as fibromyalgia, had abnormal functional connectivity of the posterior insula on functional imaging. Finally, preliminary results indicated that high-frequency electrical stimulation of the posterior insula can acutely increase pain thresholds. Conclusion: In light of the converging evidence from neuroanatomical, brain lesion, neuroimaging, and intracranial recording and stimulation as well as non-invasive stimulation studies, it appears that the insula is a critical hub for central integration and processing of painful stimuli, whose high-frequency electrical stimulation has the potential to relieve patients from the sensory and affective burden of chronic pain.

BACKGROUND Facial palsy is a rare, unexpected complication of temporal lobectomy (TL) for intractable epilepsy. Even without direct manipulation, the facial nerve fibers may be at risk of injury during supratentorial surgery, including TL. OBSERVATIONS The authors presented two cases of facial palsy after unremarkable TL. In the first case, the palsy appeared in a delayed fashion and completely resolved within weeks. In the second case, facial nerve dysfunction was observed immediately after surgery, followed by progressive recovery over 2 years. The second patient had a dehiscence of the roof of the petrous bone overlying the geniculate ganglion, which put the facial nerve at risk of bipolar coagulation thermal injury. LESSONS Two major mechanisms could explain the loss of facial nerve function after TL: surgery-related indirect inflammation of the nerve resulting in herpesvirus reactivation and delayed dysfunction (Bell’s palsy) or indirect thermal damage to the geniculate ganglion through a dehiscent petrous roof.

Functional neuroimaging studies suggest that the insular cortex-and more especially the anterior insula (aI)-is involved in attentional processes and plays a crucial role in the "salience network". However, its specific role in attentional processing remains unclear, which is partly attributable to the low temporal resolution of non-invasive neuroimaging techniques. This study aims to examine the spatio-temporal dynamics of visual target processing using intracranial EEG recorded directly from the insula. Eight epileptic patients (four women, age 18-44 years) completed a three-stimulus visual oddball task during the extraoperative invasive intracranial EEG (iEEG) monitoring of their drug-resistant seizures. Depth electrodes were implanted in ten insular lobes (5 left and 5 right) and provided a total of 59 recording contacts in the insula. Event-related potentials (ERPs) and high-gamma-band responses (GBRs) were processed offline. Permutation analyses were performed to compare ERP signals across conditions during the P300 (225-400) interval, and modulations of GBRs (70-150 Hz) were computed for separate 100 ms time windows (from 0 to 1000 ms post-stimulus) and compared across conditions using non-parametric Wilcoxon test. Target stimuli were associated with a P300 (250-338 ms) component for 39% of contacts implanted in the aI, most probably reflecting voluntary attentional processing. Amplitude was significantly greater for target than for standard stimuli for all of these contacts, and was greater than for novel stimuli for 72%. In the posterior insula (pI), 16% of contacts showed preferential responses to target stimulus in the P300 interval. Increased GBRs in response to targets were observed in 53% of aI contacts (from ≈ 200 to 300 ms) and in 43% of pI contacts (from ≈ 400 to 500 ms). This study is the first to characterize the spatio-temporal dynamics of visual target processing in the insula using iEEG. Results suggest that visual targets elicit a P300 in the aI which corresponds in latency to the P3b component, suggesting that this region is involved in top-down processing of task-relevant information. GBRs to visual targets occur earlier in the aI than in the pI, further characterizing their respective roles in voluntary attentional processing.

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4+ T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4+ T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70-/-CD4+ T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4+ T lymphocytes. CD70+CD4+ T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.

Objectives: With the current trend of aging of the population, neurosurgeons will be more and more confronted to surgical decision-making involving the elderly. Faced with this increasing demand and frailty of aged patients, a better understanding on the post-operative outcome of this growing population is warranted. The objective of the present study is to assess the post-operative outcome in regard of complications of elderly patients undergoing a craniotomy. Patients and methods: The files of consecutive patients aged 80 years old and more who underwent a craniotomy at a single institution were retrospectively reviewed. Data on demographics, surgical indication, length of surgery, operative blood loss, urgency of surgery, comorbidities using the Elixhauser comorbidity index and post-operative complications were gathered. We performed a multivariate analysis in search of risk factors for post-operative complications. Results: A total of 53 patients were included in the study. The mean age of all patients was 84 years old with the main indication for surgery being subdural hematoma. The overall complication rate was 62%, with 34% of patients suffering from a major complication and 47% from a minor complication. The mean Elixhauser comorbidity index, operative time and operative blood loss were similar to those reported in adult craniotomy series. None of the studied variables were statistically associated with the occurrence of complications in the multivariate analysis. Conclusion: Patients 80 years-old and more were found to harbour a high complication rate following craniotomy when compared to literature. Our study suggests increasing age itself remains an important risk factor for postoperative complications. Keywords: Comorbidity, Complication, Craniotomy, Elderly, Outcome

Background Epilepsy surgery is likely underutilised. Our goal was to study the utilisation of epilepsy surgery in the general population, using Canada as a model of a high-income country with universal medical coverage. Methods We systematically identified all epilepsy surgery centres in Canada that were active in 2015. A standardised questionnaire was completed by every centre. Descriptive statistics are reported. Comparisons were made to a 2003 survey of paediatric epilepsy surgery. Results Twelve adult and 11 paediatric epilepsy surgery centres were identified, performing a total of 456 and 206 surgical procedures, respectively, in 2015. Adult centres were in only six of 10 provinces; paediatric centres were in seven. Two thirds of adult centres and one third of paediatric centres were high-volume centres. Per capita volume per province varied between 7.0 and 20.5 therapeutic surgeries per million adult residents, and between 7.8 and 48.4 per million paediatric residents. Temporal lobe resections accounted for 59.8% and 33.5% of all adult and paediatric treatments, respectively. Eleven adult and nine paediatric centres possessed facilities to carry out intracranial investigations but only six and two, respectively, performed at least six intracranial implantations in 2015. There was a modest increase in the per capita number of paediatric surgeries between 2003 and 2015. Conclusions There is dramatic inter-centre and interprovincial variability in the epilepsy services available and the type of surgical interventions performed with significant gaps identified in some regions. Our findings are pivotal for the future optimisation of care offered to this vulnerable patient population.

Precise detection of brain regions harboring heightened electrical activity plays a central role in the understanding and treatment of diseases such as epilepsy. Superparamagnetic iron oxide nanoparticles (SPIONs) react to magnetic fields by aggregating and represent interesting candidates as new sensors for neuronal magnetic activity. We hypothesized that SPIONs in aqueous solution close to active brain tissue would aggregate proportionally to neuronal activity. We tested this hypothesis using an in vitro model of rat brain slice with different levels of activity. Aggregation was assessed with dynamic light scattering (DLS) and magnetic resonance imaging (MRI). We found that increasing brain slice activity was associated with higher levels of aggregation as measured by DLS and MRI, suggesting that the magnetic fields from neuronal tissue could induce aggregation in nearby SPIONs in solution. MRI signal change induced by SPIONs aggregation could serve as a powerful new tool for detection of brain electrical activity.

The insular cortex is now well-established as a potential site of epileptogenesis in patients with drug-resistant epilepsy, and its resection has been associated with good outcomes in terms of seizure control. However, given the role of the insula in sensory processing and in visceral information integration, it remains unclear whether insular cortex epilepsy and its surgery are associated with disturbances in sensory information processing and visceral sensation processes as experienced in daily life. In the present study, we examined such sensory disturbances in a group of patients (n = 17) who underwent epilepsy surgery involving a resection of the insula and compared them to a lesion-control group of patients with temporal epilepsy surgery (n = 22) and a healthy control group (n = 29) matched for age, gender, and education. Participants were assessed on the self-report “Adolescent/Adult Sensory Profile” questionnaire at least four months after surgery. Our series of one-way analyses of variance (ANOVAs) revealed that insular and temporal resections in patients with drug-refractory epilepsy were associated with a low “sensation seeking” behavior reflecting a lack of engagement with sensory inputs from the environment. Furthermore, insular resections were associated with impairments in the “active behavioral responses” for the gustatory/olfactory modalities. These preliminary findings suggest that insular resections may be associated with mild to moderate alterations in sensory processing.

Entrenched deep within the Sylvian fissure, the insula has long been considered one of the least understood regions of the human brain, in part due to its restricted accessibility. However, recent evidence suggests that the insula plays a key role in gustation, interoception, cognitive and emotional processes, and likely integrates these different functions to contribute to the homeostatic control of food intake. In the past decade, our team has identified the insula as a potential site of epileptogenicity, which can be successfully treated by microsurgical resection. While most surgeries are successful in controlling insular epileptic seizures and lead to few postoperative deficits, the subtle changes that may occur in food-related experiences are still unknown. Using a self-report questionnaire, the present study sought to fill this gap by assessing changes in appetite in patients who underwent unilateral partial or complete insular resections (n = 17) as part of their epilepsy surgery. We compared them to a group of patients who underwent temporal lobe epilepsy surgery (n = 22) as a lesion-control group. A majority (59%) of the insular patients reported an alteration in appetite, with most of these changes being characterized by a persistent reduction. Such changes were rarely reported following temporal lobectomy (14%). While they significantly differed in terms of appetite changes, both groups were similar when examining post-surgical changes in weight, diet, exercise and eating habits. Insular patients with altered appetite also showed behavioral signs of dysfunctional interoceptive and gustatory functions, corroborating the idea that these systems play a role in the regulation of feeding behaviours. This research pushes our understanding of the mechanisms underlying food intake and could lead to avenues for the treatment of eating disorders.

Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy.We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77CT; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079GA; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77CT) in the CHRNB2 gene.We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation.This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

Three decades after its introduction as an adjuvant therapeutic option in the management of selective drug-resistant epilepsy cases (DRE), vagus nerve stimulation (VNS) retains growing interest. An implantable device was first approved for epilepsy in Europe in 1994 and in the United States (US) in 1997. Subsequent modifications improved the safety and the efficacy of the system. The most recent application of vagal neurostimulation is represented by transcutaneous devices that are claimed to have strong therapeutic potential. In this review, we sought to analyze the most meaningful available data describing the indications, safety and efficacy of the different approaches of VNS in clinical practice. Therefore, we identified studies reporting VNS efficacy and/or safety in epilepsy and its comorbidities from January 1990 to February 2020 from various databases including PubMed, Scopus, Cochrane, US government databases and VNS manufacturer published resources. In general, VNS efficacy becomes optimal around the sixth month of treatment and a 50-100 % seizure frequency reduction is achieved in approximately 45-65 % of the patients. However, some clinically relevant differences have been reported with specific factors such as epilepsy etiology or type, patient age as well as the delay of VNS therapy onset. VNS efficacy on seizure frequency has been demonstrated in both children and adults, in lesional and non-lesional cases, in focal and generalized epilepsies, on both seizures and epilepsy comorbidities. Regarding the latter, VNS can lead to an improvement of about 25-35 % in depression scores, 35 % in anxiety scores and 25 % in mood assessment scores. If non-invasive devices are undeniably safer, their efficacy is limited due to the scarcity of large cohort studies and the disparity of methodological approaches (study design and stimulation parameters). Overall, we believe that there is a progress margin for improving the safety of implantable devices and, above all, the effectiveness of the various VNS approaches.

Significance: The practicality of optical methods detecting tissue optical contrast (absorption, elastic and inelastic scattering, fluorescence) for surgical guidance is limited by interferences from blood pooling and the resulting partial or complete inability to interrogate cortex and blood vessels. Aim: A multispectral diffuse reflectance technique was developed for intraoperative brain imaging of hemodynamic activity to automatically discriminate blood vessels, cortex, and bleeding at the brain surface. Approach: A manual segmentation of blood pooling, cortex, and vessels allowed the identification of a frequency range in hemoglobin concentration variations associated with high optical signal in blood vessels and cortex but not in bleeding. Reflectance spectra were then used to automatically segment areas with and without hemodynamic activity as well as to discriminate blood from cortical areas. Results: The frequency range associated with low-frequency hemodynamics and respiratory rate (0.03 to 0.3 Hz) exhibits the largest differences in signal amplitudes for bleeding, blood vessels, and cortex. A segmentation technique based on simulated reflectance spectra initially allowed discrimination of blood (bleeding and vessels) from cortical tissue. Then, a threshold applied to the low-frequency components from deoxyhemoglobin allowed the segmentation of bleeding from vessels. A study on the minimum acquisition time needed to discriminate all three components determined that ∼25 s was necessary to detect changes in the low-frequency range. Other frequency ranges such as heartbeat (1 to 1.7 Hz) can be used to reduce the acquisition time to few seconds but would necessitate optimizing instrumentation to ensure larger signal-to-noise ratios are achieved. Conclusions: A method based on multispectral reflectance signals and low-frequency hemoglobin concentration changes can be used to distinguish bleeding, blood vessels, and cortex. This could be integrated into fiber optic probes to enhance signal specificity by providing users an indication of whether measurements are corrupted by blood pooling, an important confounding factor in biomedical optics applied to surgery.

Background Precise detection of zones of increased brain activity is a crucial aspect in the delineation of the cortical region responsible for epilepsy (epileptic focus). When possible, removal of this area can lead to improved control of epilepsy or even its cure. This study explores a new method of detection of electrical brain activity based on the surgical implantation of iron oxide superparamagnetic nanoparticles (SPIONs). By their magnetic nature, SPIONs tend to aggregate in the presence of magnetic fields. This study aims to demonstrate if brain’s magnetic fields could change the aggregation status of SPIONs in a rat model. Methods Plastic containers (capsules) containing SPIONs in aqueous suspension were implanted over the cortex of either rats rendered epileptic or naive rats (sham). A model of focal epilepsy using cortical penicillin injection was used for the epileptic rats. Capsules not implanted in rats served as control. Using magnetic resonance imaging (MRI), the aggregation status of SPIONs contained in the capsules was assessed via measurement of the T2 relaxivity time of the solutions. Results Eight Rats were used for the experiments, with 4 rats in each group (epileptic and sham). One Rat in the sham group died immediately after surgery and 3 rats failed to demonstrate the expected behavior after intervention (2 rats in epileptic group with limited observable seizures and 1 rat in the sham group having repeated seizures). T2 of the control capsules were significantly lower than those implanted in rats (146 ms vs 7.6 ms, p Conclusions SPIONs implanted over the cortex of active brain showed an increased aggregation status, confirming their potential as a new marker for brain activity. One of the main advantages of SPIONs is that their aggregation status can be measured at a distance with MRI, taking advantage of its high spatial resolution and imaging capacities. The current model was suboptimal to confirm if epileptic activity can be differentiated from normal brain activity using SPIONs.

We present an intraoperative hyperspectral imaging system and the hemodynamics data acquired in 12 epileptic patients, allowing detection of the hemodynamic response function associated with interictal spikes, and localization of the area with the highest epileptic activity.

International audience; The presence of B lymphocyte-associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell-dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM+ B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte-targeting therapies for the treatment of MS. © 2019 The Authors.

Superparamagnetic iron oxide nanoparticles (SPIONs) consist of nanosized metallic-based particles with unique magnetic properties. Their potential in both diagnostic and therapeutic applications in the CNS is at the source of an expanding body of the literature in recent years. Colloidal stability of nanoparticles represents their ability to resist aggregation and is a central aspect for the use of SPION in biological environment such as the CNS. This review gives a comprehensive update of the recent developments and knowledge on the determinants of colloidal stability of SPIONs in the CNS. Factors leading to aggregate formation and the repercussions of colloidal instability of SPION are reviewed in detail pertaining to their use in the CNS.

Objective For patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone is more arduous, and intracranial electroencephalography (EEG) (icEEG) is frequently required. Planning for icEEG is dependent on combined data from multiple noninvasive modalities. We report the negative impact of lack of integration of magnetoencephalography (MEG) in the presurgical workup in NLRFE. Methods Observational MEG case series involving 31 consecutive patients with NLRFE in an academic epilepsy center. For various reasons, MEG data were not analyzed in a timely manner to be included in the decision-making process. The presumed impact of MEG was assessed retrospectively. Results Magnetoencephalography would have changed the initial management in 21/31 (68%) had MEG results been available by reducing the number of intracranial electrodes, modifying their position, allowing for direct surgery, canceling the intracranial study, or providing enough evidence to justify one. Good surgical outcome was achieved in 11 out of 17 patients who proceeded to epilepsy surgery. Nine out of eleven had MEG clusters corresponding to the resection area, and MEG findings would have allowed for direct surgery (avoiding icEEG) in 2/11. Six patients had poor outcome including three patients where MEG would have significantly changed the outcome by modifying the resection margin. Magnetoencephalography provided superior information in 3 patients where inadequate coverage precluded accurate mapping of the epileptogenic zone. Conclusion In this single center retrospective study, MEG would have changed patient management, icEEG planning, and surgical outcome in a significant percentage of patients with NLRFE and should be considered in the presurgical workup in those patients.