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Cerebrospinal fluid (CSF) leak through petrosal air cells is a known complication after drilling the posterior wall of the internal acoustic canal (IAC) for resection of vestibular schwannoma (VS). Whereas mild pneumocephalus is common after retrosigmoid craniotomy, tension pneumocephalus has been rarely documented. To testify a case of fatal tension pneumocephalus after VS resection in a patient with ventriculo-peritoneal (VP) shunt and to propose possible recommendations to limit the risk of this dramatic complication. A case of fatal tension pneumocephalus after VS resection in presence of hidden CSF fistula is illustrated with pre- and post-operative images. In the uneventful situation of concomitant post-operative CSF fistula in presence of VP shunt, tension pneumocephalus may occur. The negative pressure created by the shunt system and the presence of osteo-dural defect allow the air to enter and, at the same time, prevent the outflow. After VS resection, tension pneumocephalus can occur as a consequence of CSF fistula from petrosal air cells in the presence of functioning VP shunt. Precautions as pre-operative increase to 'virtual-off' the pressure of the valve, subsequences CT scans after surgery and sealing of the petrous air cells are recommended to avoid such as fatal complication. [ABSTRACT FROM AUTHOR]

Since 2017, hormone-negative pituitary neuroendocrine tumors expressing the steroidogenic factor SF1 have been recognized as gonadotroph tumors (GnPT) but have been poorly studied. To further characterize their bio-clinical spectrum, 54 GnPT defined by immunostaining for FSH and/or LH (group 1, n = 41) or SF1 only (group 2, n = 13) were compared and studied for SF1, βFSH, βLH, CCNA2, CCNB1, CCND1, caspase 3, D2R, and AIP gene expression by qRT-PCR. Immunohistochemistry for AIP and/or D2R was performed in representative cases. Overall, patients were significantly younger in group 1 (P = 0.040 vs group 2), with a similar trend excluding recurrent cases (P = 0.078), and no significant difference in gender, tumor size, invasion or Ki67. SF1 expression was similar in both groups but negatively correlated with the patient's age (P = 0.013) and positively correlated with βLH (P < 0.001) expression. Beta-FSH and AIP were significantly higher in group 1 (P = 0.042 and P = 0.024, respectively). Ki67 was unrelated to gonadotroph markers but positively correlated with CCNB1 (P = 0.001) and negatively correlated with CCND1 (P = 0.008). D2R and AIP were strongly correlated with each other (P < 0.001), and both positively correlated with SF1, βFSH, βLH, and CCND1. AIP immunopositivity was frequently observed in both groups, with a similar median score, and unrelated to Ki67. D2R immunostaining was best detected with a polyclonal antibody and mostly cytoplasmic. This study indicates that hormone-negative GnPT tend to occur in older patients but do not significantly differ from other GnPT in terms of invasion or proliferation. It also points out the current limits of D2R immunostaining in such tumors. [ABSTRACT FROM AUTHOR]

Background: Gross total resection, when possible, is the first crucial treatment for high-grade gliomas, as it has been demonstrated to be associated with longer survival. Different intraoperative tools, such as neuronavigation, fluorescent agents, and intra-operative ultrasound, have been developed to help neurosurgeons to extend the resection. Methods: We describe the high-magnification microsurgery technique used during the first surgical removal for high-grade gliomas. We illustrate the key anatomical "markers" of normal brain parenchyma, which guide the surgery. Conclusion: High-magnification microsurgery is an anatomically based approach that allows the identification of key anatomical "markers" of normal brain parenchyma in order to resect high-grade gliomas safely and effectively. [ABSTRACT FROM AUTHOR]

Introduction: The plasticity of the neural circuits after injuries has been extensively investigated over the last decades. Transcallosal microsurgery for lesions affecting the third ventricle offers an interesting opportunity to investigate the whole-brain white matter reorganization occurring after a selective resection of the genu of the corpus callosum (CC). Method: Diffusion MRI (dMRI) data and neuropsychological testing were collected pre- and postoperatively in six patients with colloid cysts, surgically treated with a transcallosal-transgenual approach. Longitudinal connectometry analysis on dMRI data and graph analysis on structural connectivity matrix were implemented to analyze how white matter pathways and structural network topology reorganize after surgery. Results: Although a significant worsening in cognitive functions (e.g., executive and memory functioning) at early postoperative, a recovery to the preoperative status was observed at 6 months. Connectometry analysis, beyond the decrease of quantitative anisotropy (QA) near the resection cavity, showed an increase of QA in the body and forceps major CC subregions, as well as in the left intra-hemispheric corticocortical associative fibers. Accordingly, a reorganization of structural network topology was observed between centrality increasing in the left hemisphere nodes together with a rise in connectivity strength among mid and posterior CC subregions and cortical nodes. Conclusion: A structural reorganization of intra- and inter-hemispheric connective fibers and structural network topology were observed following the resection of the genu of the CC. Beyond the postoperative transient cognitive impairment, it could be argued anterior CC resection does not preclude neural plasticity and may subserve the long-term postoperative cognitive recovery. [ABSTRACT FROM AUTHOR]

Introduction: Pre-surgical mapping is clinically essential in the surgical management of brain tumors to preserve functions. A common technique to localize eloquent areas is functional magnetic resonance imaging (fMRI). In tumors involving the peri-rolandic regions, the finger tapping task (FTT) is typically administered to delineate the functional activation of hand-knob area. However, its selectivity may be limited. Thus, here, a novel cue-induced fMRI task was tested, the visual-triggered finger movement task (VFMT), aimed at eliciting a more accurate functional cortical mapping of the hand region as compared with FTT. Method: Twenty patients with glioma in the peri-rolandic regions underwent pre-operative mapping performing both FTT and VFMT. The fMRI data were analyzed for surgical procedures. When the craniotomy allowed to expose the motor cortex, the correspondence with intraoperative direct electrical stimulation (DES) was evaluated through sensitivity and specificity (mean sites = 11) calculated as percentage of true-positive and true-negative rates, respectively. Results: Both at group level and at single-subject level, differences among the tasks emerged in the functional representation of the hand-knob. Compared with FTT, VFMT showed a well-localized activation within the hand motor area and a less widespread activation in associative regions. Intraoperative DES confirmed the greater specificity (97%) and sensitivity (100%) of the VFMT in determining motor eloquent areas. Conclusion: The study provides a novel, external-triggered fMRI task for pre-surgical motor mapping. Compared with the traditional FTT, the new VFMT may have potential implications in clinical fMRI and surgical management due to its focal identification of the hand-knob region and good correspondence to intraoperative DES. [ABSTRACT FROM AUTHOR]

Purpose: People with drug-refractory epilepsy are potential candidates for surgery. In many cases, epileptogenic zone localization requires intracranial investigations, e.g., via ElectroCorticoGraphy (ECoG), which uses subdural electrodes to map eloquent areas of large cortical regions. Precise electrodes localization on cortical surface is mandatory to delineate the seizure onset zone. Simple thresholding operations performed on patients' computed tomography (CT) volumes recognize electrodes but also other metal objects (e.g., wires, stitches), which need to be manually removed. A new automated method based on shape analysis is proposed, which provides substantially improved performances in ECoG electrodes recognition. Methods: The proposed method was retrospectively tested on 24 CT volumes of subjects with drug-refractory focal epilepsy, presenting a large number (> 1700) of round platinum electrodes. After CT volume thresholding, six geometric features of voxel clusters (volume, symmetry axes lengths, circularity and cylinder similarity) were used to recognize the actual electrodes among all metal objects via a Gaussian support vector machine (G-SVM). The proposed method was further tested on seven CT volumes from a public repository. Simultaneous recognition of depth and ECoG electrodes was also investigated on three additional CT volumes, containing penetrating depth electrodes. Results: The G-SVM provided a 99.74% mean classification accuracy across all 24 single-patient datasets, as well as on the combined dataset. High accuracies were obtained also on the CT volumes from public repository (98.27% across all patients, 99.68% on combined dataset). An overall accuracy of 99.34% was achieved for the recognition of depth and ECoG electrodes. Conclusions: The proposed method accomplishes automated ECoG electrodes localization with unprecedented accuracy and can be easily implemented into existing software for preoperative analysis process. The preliminary yet surprisingly good results achieved for the simultaneous depth and ECoG electrodes recognition are encouraging. Ethical approval n°NCT04479410 by "IRCCS Neuromed" (Pozzilli, Italy), 30th July 2020. [ABSTRACT FROM AUTHOR]

Hydrocephalus (HC) can be associated with vestibular schwannoma (VS) at presentation. Although spontaneous resolution of HC after VS removal is reported, first-line treatment is varied including preoperative ventriculoperitoneal (VP) shunt, external ventricular drainage (EVD), or lumbar drainage (LD). We performed a systematic review to clarify optimal management of HC associated with VS at presentation, as well as characteristics of patients with initial and persistent HC after VS removal, and prevalence of HC associated with VS. Fourteen studies were included. Patients were grouped according to the timing of HC treatment. The overall rate of VP shunts was 19.4%. Among patients who received VS removal as first-line treatment, 6.9% underwent permanent shunts. In a subgroup of 132 patients (studies with no-aggregate data), t test analysis for mean tumor size (P = 0.02) and mean CSF protein level (P < 0.001) demonstrated statistically significant differences between patients with resolved HC (3.48 cm and 201 mg/dL) and patients with persistent HC (2.46 cm and 76.8 mg/dL) after VS resection. Transient treatment of HC using EVD or LD further resolved the HC in 87.5% and 82.9% of patients, respectively, before and after VS removal. The overall prevalence of HC associated with VS in a population of 2336 patients was 9.3%. Schwannoma removal as first-line treatment is justified by its low rate of persistent HC requiring VP shunt (roughly 7%). Patients with smaller VS and lower CSF proteins present higher risk of persistent HC after schwannoma removal. Temporary treatment of HC contributes to its resolution, both before and after VS removal. [ABSTRACT FROM AUTHOR]

Background: Intracellular Ca2+ modulates several microglial activities, such as proliferation, migration, phagocytosis, and inflammatory mediator secretion. Extracellular ATP, the levels of which significantly change during epileptic seizures, activates specific receptors leading to an increase of intracellular free Ca2+ concentration ([Ca2+]i). Here, we aimed to functionally characterize human microglia obtained from cortices of subjects with temporal lobe epilepsy, focusing on the Ca2+-mediated response triggered by purinergic signaling.Methods: Fura-2 based fluorescence microscopy was used to measure [Ca2+]i in primary cultures of human microglial cells obtained from surgical specimens. The perforated patch-clamp technique, which preserves the cytoplasmic milieu, was used to measure ATP-evoked Ca2+-dependent whole-cell currents.Results: In human microglia extracellular ATP evoked [Ca2+]i increases depend on Ca2+ entry from the extracellular space and on Ca2+ mobilization from intracellular compartments. Extracellular ATP also induced a transient fivefold potentiation of the total transmembrane current, which was completely abolished when [Ca2+]i increases were prevented by removing external Ca2+ and using an intracellular Ca2+ chelator. TRAM-34, a selective KCa3.1 blocker, significantly reduced the ATP-induced current potentiation but did not abolish it. The removal of external Cl- in the presence of TRAM-34 further lowered the ATP-evoked effect. A direct comparison between the ATP-evoked mean current potentiation and mean Ca2+ transient amplitude revealed a linear correlation. Treatment of microglial cells with LPS for 48 h did not prevent the ATP-induced Ca2+ mobilization but completely abolished the ATP-mediated current potentiation. The absence of the Ca2+-evoked K+ current led to a less sustained ATP-evoked Ca2+ entry, as shown by the faster Ca2+ transient kinetics observed in LPS-treated microglia.Conclusions: Our study confirms a functional role for KCa3.1 channels in human microglia, linking ATP-evoked Ca2+ transients to changes in membrane conductance, with an inflammation-dependent mechanism, and suggests that during brain inflammation the KCa3.1-mediated microglial response to purinergic signaling may be reduced. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor alpha (PPARa) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARa in additional phenotypes of pituitary adenomas (PA), the relationship between PPARa and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARa agonists on lactotroph cells. Seventy-five human PA - 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) - were characterised for PPARa and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARa was expressed in a majority of PA. PPARa immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p = 0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p = 0.003). PPARa expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100-200 µM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARa is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARa agonists. [ABSTRACT FROM AUTHOR]

Summary: Objective: γ‐Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in adult central nervous system, and profound alterations of GABA receptor functions are linked to temporal lobe epilepsy (TLE). Here we describe the functional relationships between GABA receptors type B (GABABR) and type A (GABAAR) in human temporal cortex and how TLE affects this aspect of GABAergic signaling. Methods: Miniature inhibitory postsynaptic currents (mIPSCs) were recorded by patch‐clamp techniques from human L5 pyramidal neurons in slices from temporal cortex tissue obtained from surgery. Results: We describe a constitutive functional crosstalk between GABABRs and GABAARs in human temporal layer 5 pyramidal neurons, which is lost in epileptic tissues. The activation of GABABRs by baclofen, in addition to the expected reduction of mIPSC frequency, produced, in cortex of nonepileptic patients, the prolongation of mIPSC rise and decay times, thus increasing the inhibitory net charge associated with a single synaptic event. Block of K+ channels did not prevent the increase of decay time and charge. Protein kinase A (PKA) blocker KT5720 and pertussis toxin inhibited the action of baclofen, whereas 8Br‐cAMP mimicked the GABABR action. The same GABABR‐mediated modulation of GABAARs was observed in pyramidal neurons of rat temporal cortex, with both PKA and PKC involved in the process. In cortices from TLE patients and epileptic rats, baclofen lost its ability to modulate mIPSCs. Significance: Our results highlight the association of TLE with functional changes of GABAergic signaling that may be related to seizure propagation, and suggest that the selective activation of a definite subset of nonpresynaptic GABABRs may be therapeutically useful in TLE. [ABSTRACT FROM AUTHOR]

We have previously shown that in seven drug-resistant epilepsy patients, both reaching-grasping of objects and the mere observation of those actions did desynchronize subdural electrocorticographic (ECoG) alpha (8-13 Hz) and beta (14-30) rhythms as a sign of cortical activation in primary somatosensory-motor, lateral premotor and ventral prefrontal areas (Babiloni et al., 2016a). Furthermore, that desynchronization was greater during action execution than during its observation. In the present exploratory study, we reanalyzed those ECoG data to evaluate the proof-of-concept that lagged linear connectivity (LLC) between primary somatosensory-motor, lateral premotor and ventral prefrontal areas would be enhanced during the action execution compared to the mere observation due to a greater flow of visual and somatomotor information. Results showed that the delta-theta (<8 Hz) LLC between lateral premotor and ventral prefrontal areas was higher during action execution than during action observation. Furthermore, the phase of these delta-theta rhythms entrained the local event-related connectivity of alpha and beta rhythms. It was speculated the existence of a multi-oscillatory functional network between high-order frontal motor areas which should be more involved during the actual reaching-grasping of objects compared to its mere observation. Future studies in a larger population should cross-validate these preliminary results. [ABSTRACT FROM AUTHOR]

KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAFv600E mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAFv600E in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAFv600E mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAFv600E mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss. [ABSTRACT FROM AUTHOR]

Video-EEG monitoring with intracranial subdural electrodes is a useful assessment tool for the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy. We aimed at assessing the morbidity related to electrode implantation and the surgical outcome in patients who underwent epilepsy surgery after intracranial EEG monitoring. All patients ( N = 58) admitted to our Epilepsy Surgery Centre for drug-resistant focal epilepsy who underwent resective surgery after intracranial monitoring with subdural electrodes and were followed up for at least 2 years were included in the study. Their mean age was 30.4 years (range 8-60 years), 25 (43 %) were female, and 44 (76 %) had a preoperatively detected structural lesion. The mean duration of invasive recording was 2.3 days (range 1-14 days). Extraoperative ECoG allowed the identification of the epileptogenic focus in all cases. The temporal lobe was involved in 21 (36 %) patients, whereas extratemporal foci were identified in 24 (41 %) patients. Thirteen patients (23 %) had multilobar involvement. Functional brain mapping was performed in 15 (26 %) patients. Transient complications related to electrode implantation occurred in three patients. Among patients with evidence of lesion on preoperative MRI, lesionectomy alone was performed in 12 cases (27 %), while it was combined with tailored cortical resection in the remaining cases. Tailored cortical resection was also performed in patients without evidence of lesion on MRI. After resective surgery, transient neurological deficits occurred in five cases, while another patient experienced permanent lateral homonymous hemianopia. At the last follow-up observation, 34 (57 %) patients were seizure-free (Engel class I). This study suggests that invasive EEG recording with subdural electrodes may be useful and fairly safe for many candidates for epilepsy surgery. [ABSTRACT FROM AUTHOR]

We previously found that the endogenous anticonvulsant adenosine, acting through A2A and A3 adenosine receptors (ARs), alters the stability of currents (IGABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether AR5 alter the stability (desensitization) of IGABA expressed in focal cortical dysplasia (FCD) and in penglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABAA receptors revealed instability, manifested by a large IGABA rundown, which in most of the oocytes (≈70%) was obviously impaired by the new A2A antagonists ANR82, ANR94, and ANR152. In most MILE tissue-microtransplanted oocytes, a new A3 receptor antagonist (ANR235) significantly improved IGABA stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered IGABA rundown on ANR94 treatment. Our findings indicate that antagonizing A2A and A3 receptors increases the IGABA stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy. [ABSTRACT FROM AUTHOR]

Background: Ictal asystole (IA) is a rare event observed in people with epilepsy (PwE). Clinical and IA video-electroencephalographic findings may be helpful in screening for high-risk subjects. Methods: From all PwE undergoing video-EEG for presurgical evaluation between 2000 and 2019, we retrospectively selected those with at least one IA (R–R interval of ≥3 s during a seizure). Results: IA was detected in eight out of 1088 (0.73%) subjects (mean age: 30 years; mean epilepsy duration: 9.6 years). Four out of them had a history of atonic falls. No patients had cardiac risk factors or cardiovascular diseases. Seizure onset was temporal (n = 5), temporo-parietal (n = 1) or frontal (n = 2), left-sided and right-sided in five and two patients, respectively. In one case a bilateral temporal independent seizure onset was recorded. IA was recorded in 11 out of 18 seizures. Mean IA duration was 13 s while mean IA latency from seizure onset was 26.7 s. Symptoms related to IA were observed in all seizures. Conclusion: IA is a rare and self-limiting event often observed during video-EG in patients with a history of atonic loss of consciousness and/or tardive falls in the course of a typical seizure. [ABSTRACT FROM AUTHOR]