SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain.

The SynGAP protein is a major regulator of synapse biology and neural circuit function. Genetic variants linked to epilepsy and intellectual disability disrupt synaptic function and neural excitability. SynGAP has been involved in multiple signaling pathways and can regulate small GTPases with very different roles. Yet, the molecular bases behind this pleiotropy are poorly understood. We hypothesize that different SynGAP isoforms will mediate different sets of functions and that deciphering their spatio-temporal expression and subcellular localization will accelerate understanding their multiple functions. Using isoform-specific antibodies recognizing SynGAP in mouse and human samples we found distinctive developmental expression patterns for all SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP-α1 isoforms, which directly bind to postsynaptic density-95, in cortex and hippocampus during the first 2 weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non-synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non-synaptic to a mostly postsynaptic density localization with age and ß isoforms were always found enriched in non-synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy.

[Isocitrate dehydrogenase type I mutation as a prognostic factor in glioblastoma and a literature review]. / Importancia de la mutación de la isocitrato deshidrogenasa tipo I como factor pronóstico en pacientes con glioblastomas y revisión de la literatura.

OBJECTIVE: Treatment response and prognosis in glioblastoma (GBM) tumours can differ among patients, highlighting the growing relevance of genetic biomarkers to differentiate glioblastoma sub-types. The biomarker isocitrate dehydrogenase (IDH1) is currently receiving considerable attention. The objective of this work was to analyse the clinical and prognostic differences between glioblastomas with and without the IDH1 mutation. METHODS: A retrospective study was performed on patients with GBM who underwent surgery between 2007 and 2012. The inclusion criteria were: patient age between 18-85 years who underwent surgery for the first time with complete macroscopic resection, complete adjuvant treatment with chemotherapy and radiotherapy, and a Karnofsky performance score>70. RESULTS: A total of 61 patients (36 males/25 famales) were included and with a mean age of 62.3 years. An IDH1mutation was found in 14 patients (23%). Median survival in patients with the IDH1 mutation (IDH1-m) was 23.6 months compared with 11.9 months in those with the wild type IDH1 (IDH1-wt) (P=.028). Disease onset in IDH1-m patients tended to be at a younger age, 58.7 vs. 63.4 years, but this difference was not statistically significant. CONCLUSION: Glioblastomas with IDH1-m should be considered a different entity from the IDH1-wt, as their natural history and prognosis differ. In the near future we should be classified glioblastomas based on the presence of the IDH1 mutation.

[Spinal cord metastasis from gliosarcoma. Case report and review of the literature]. / Metástasis medulares de gliosarcoma. Presentación de un caso y revisión de la literatura.

INTRODUCTION: Gliosarcoma is a rare neoplasm of the central nervous system, similar to glioblastoma multiforme. In contrast to glioblastoma, it is characterised by its propensity for extracranial metastasis (11% of the cases) due to its sarcomatous component. Intramedullary metastasis from primary gliosarcoma is extremely rare. CASE REPORT: A patient who had surgery for primary cerebral gliosarcoma developed paraparesis during the course of the disease. A magnetic resonance image showed an intramedullary spinal cord metastasis requiring surgical treatment. This article reviews the literature on intramedullary spinal cord metastasis from gliosarcoma, and highlights the characteristics, treatment and overall survival. CONCLUSIONS: Only 4 cases of intramedullary gliosarcoma metastasis are described in the literature. This extremely rare entity should be suspected with the onset of spinal cord symptoms during the course of primary cerebral gliosarcoma.

Long-Term Results of Cortical Motor Stimulation for Neuropathic Peripheral and Central Pain: Real-World Evidence From Two Independent Centers.

BACKGROUND AND OBJECTIVES: Cortical motor stimulation (CMS) is used to modulate neuropathic pain. The literature supports its use; however, short follow-up studies might overestimate its real effect. This study brings real-world evidence from two independent centers about CMS methodology and its long-term outcomes. METHODS: Patients with chronic refractory neuropathic pain were implanted with CMS. The International Classification of Headache Disorders 3rd Edition was used to classify craniofacial pain and the Douleur Neuropathique en 4 Questions Scale score to explore its neuropathic nature. Demographics and clinical and surgical data were collected. Pain intensity at 6, 12, and 24 months and last follow-up was registered. Numeric rating scale reduction of ≥50% was considered a good response. The Clinical Global Impression of Change scale was used to report patient satisfaction. RESULTS: Twelve males (38.7%) and 19 females (61.3%) with a mean age of 55.8 years (±11.9) were analyzed. Nineteen (61.5%) were diagnosed from painful trigeminal neuropathy (PTN), and seven (22.5%) from central poststroke pain. The mean follow-up was 51 months (±23). At 6 months, 42% (13/31) of the patients were responders, all of them being PTN (13/19; 68.4%). At last follow-up, only 35% (11/31) remained responders (11/19 PTN; 58%). At last follow-up, the global Numeric rating scale reduction was 34% ( P = .0001). The Clinical Global Impression of Change scale punctuated 2.39 (±0.94) after 3 months from the surgery and 2.95 (±1.32) at last follow-up ( P = .0079). Signs of suspicious placebo effect were appreciated in around 40% of the nonresponders. CONCLUSION: CMS might show long-term efficacy for neuropathic pain syndromes, with the effect on PTN being more robust in the long term. Multicentric clinical trials are needed to confirm the efficacy of this therapy for this and other conditions.

Navigated intraoperative ultrasound in neuro-oncology: volumetric accuracy and correlation with high-field MRI.

OBJECTIVE: The use of intraoperative techniques to detect residual tumors has recently become increasingly important. Intraoperative MRI has long been considered the gold standard; however, it is not widely used because of high equipment costs and long acquisition times. Consequently, real-time intraoperative ultrasound (ioUS), which is much less expensive than MRI, has gained popularity. The aim of the present study was to evaluate the capacity of ioUS to accurately determine the primary tumor volume and detect residual tumors. METHODS: A prospective study of adult patients who underwent surgery for intra-axial brain tumors between November 2017 and October 2020 was performed. Navigated intraoperative ultrasound (nioUS) of the brain was used to guide tumor resection and to detect the presence of residual disease. Both convex (5-8 MHz) and linear array (6-13 MHz) probes were used. Tumor volume and residual disease were measured with nioUS and compared with MR images. A linear regression model based on a machine learning pipeline and a Bland-Altman analysis were used to assess the accuracy of nioUS versus MRI. RESULTS: Eighty patients (35 females and 45 males) were included. The mean age was 58 years (range 25-80 years). A total of 88 lesions were evaluated; there were 64 (73%) gliomas, 19 (21.6%) metastases, and 5 (5.7%) other tumors, mostly located in the frontal (41%) and temporal (27%) lobes. Most of the tumors (75%) were perfectly visible on ioUS (grade 3, Mair grading system), except for those located in the insular lobe (grade 2). The regression model showed a nearly perfect correlation (R2 = 0.97, p < 0.001) between preoperative tumor volumes from both MRI and nioUS. Ultrasonographic visibility significantly influenced this correlation, which was stronger for highly visible (grade 3) tumors (p = 0.01). For residual tumors, the correlation between postoperative MRI and nioUS was weaker (R2 = 0.78, p < 0.001) but statistically significant. The Bland-Altman analysis showed minimal bias between the two techniques for pre- and postoperative scenarios, with statistically significant results for the preoperative concordance. CONCLUSIONS: The authors' findings show that most brain tumors are well delineated by nioUS and almost perfectly correlated with MRI-based measurements both pre- and postoperatively. These data support the hypothesis that nioUS is a reliable intraoperative technique that can be used for real-time monitoring of brain tumor resections and to perform volumetric analysis of residual disease.

Long-term outcomes of deep brain stimulation for treatment-resistant schizophrenia: Exploring potential targets.

BACKGROUND: Schizophrenia is a complex and disabling disorder. Around 30% of patients have treatment-resistant schizophrenia (TRS). OBJECTIVE: This study summarizes the outcomes after three years follow-up of the first series of patients with TRS treated with deep brain stimulation (DBS) and discuss surgical, clinical and imaging analysis. METHODS: Eight patients with TRS treated with DBS in the nucleus accumbens (NAcc) or the subgenual cingulate gyrus (SCG) were included. Symptoms were rated with the PANSS scale and normalized using the illness density index (IDI). A reduction in IDI-PANSS of ≥25% compared to baseline was the criterion of good response. The volume of activated tissue was calculated to perform a connectomic analysis for each patient. An estimation of the tracts and cortical areas modulated was generated. RESULTS: Five women and three men were analyzed. After 3 years' follow-up, positive symptoms improved in 50% of the SCG group and 75% of the NAcc group (p = 0.06), and general symptoms improved in 25% and 50% respectively (p = 0.06). The SCG group showed activation of the cingulate bundle and modulation of orbitofrontal and frontomesial regions; in contrast, the NAcc group showed activation of the ventral tegmental area projections pathway and modulation of regions associated with the "default mode network" (precuneus) and Brodmann areas 19 and 20. CONCLUSIONS: These results showed a trend toward improvement for positive and general symptoms in patients with TRS treated with DBS. The connectomic analysis will help us understand the interaction of this treatment with the disease to pursue future trial designs.

Neuronavigated Ultrasound in Neuro-Oncology: A True Real-Time Intraoperative Image.

OBJECTIVE: Ultrasound is considered a real-time imaging method in neuro-oncology because of its highly rapid image acquisition time. However, to our knowledge, there are no studies that analyze the additional surgical time that it requires. METHODS: A prospective study of 100 patients who underwent intra-axial brain tumor resection with navigated intraoperative ultrasound. The primary outcomes were lesion visibility grade on ultrasound and concordance with preoperative magnetic resonance imaging (MRI) scan, intraoperative ultrasound usage time, and percentage of tumor resection on ultrasound and comparison with postoperative MRI scan. RESULTS: The breakdown of patients included the following: 53 high-grade gliomas, 26 metastases, 14 low-grade gliomas, and 7 others. Ninety-six percent of lesions were clearly visualized. The tumor border was clearly delimited in 71%. Concordance with preoperative MRI scan was 78% (P < 0.001). The mean time ± SD for sterile covering of the probe was 2.16 ± 0.5 minutes, and the mean image acquisition time was 2.49 ± 1.26 minutes. Insular tumor location, low-grade glioma, awake surgery, and recurrent tumor were statistically associated with an increased ultrasound usage time. Ultrasound had a sensitivity of 94.4% and a specificity of 100% for residual tumor detection. CONCLUSIONS: Neuronavigated ultrasound can be considered a truly real-time intraoperative imaging method because it does not increase surgical time significantly and provides optimal visualization of intra-axial brain lesions and residual tumor.

RNA sequencing and Immunohistochemistry Reveal ZFN7 as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP-negative Glioblastoma.

PURPOSE: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. EXPERIMENTAL DESIGN: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. RESULTS: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. CONCLUSIONS: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

Intraoperative imaging in the neurosurgery operating theatre: A review of the most commonly used techniques for brain tumour surgery. / Imagen intraoperatoria en el quirófano de neurocirugía: revisión de las técnicas más empleadas para la cirugía de los tumores cerebrales.

INTRODUCTION: New intraoperative imaging techniques, which aim to improve tumour resection, have been implemented in recent years in brain tumour surgery, although they lead to an increase in resources. In order to carry out an update on this topic, this manuscript has been drafted by a group from the Sociedad Española de Neurocirugía (Spanish Society of Neurosurgery). MATERIAL AND METHODS: Experts in the use of each one of the most-used intraoperative techniques in brain tumour surgery were presented with a description of the technique and a brief review of the literature. Indications for use, their advantages and disadvantages based on clinical experience and on what is published in the literature will be described. RESULTS: The most robust intraoperative imaging technique appears to be low- and high-field magnetic resonance imaging, but this is the technique which results in the greatest expenditure. Intraoperative ultrasound navigation is portable and less expensive, but it provides poorer differentiation of high-grade tumours and is observer-dependent. The most-used fluorescence techniques are 5-aminolevulinic acid for high-grade gliomas and fluorescein, useful in lesions which rupture the blood-brain barrier. Last of all, intraoperative CT is more versatile in the neurosurgery operating theatre, but it has fewer indications in neuro-oncology surgery. CONCLUSIONS: Intraoperative imaging techniques are used with increasingly greater frequency in brain tumour surgery, and the neurosurgeon should assess their possible use depending on their resources and the needs of each patient.

Intraoperative Use and Benefits of Tractography in Awake Surgery Patients.

OBJECTIVE: The present study analyzed the benefits of the use of tractography in the preoperative and intraoperative scenarios. METHODS: We present a prospective cohort study with 2 groups of patients who had undergone awake surgery for brain tumor resection. A control group for which no intraoperative navigated diffusion tensor imaging (DTI) was used (non-DTI group) and the case group (DTI group). The operative time, complete tumor resection, and neurological postoperative deficits were measured as primary outcomes. A secondary analysis was performed to determine the power of preoperative DTI to predict for complete tumor resection. RESULTS: A total of 37 patients were included, 18 in the non-DTI group and 19 in the DTI group. No differences were found between the 2 groups for sex, mean age, tumor histological findings, and preoperative mean tumor volume. The awake surgical time in the non-DTI group was 119.8 ± 31.1 minutes and 93.6 ± 12.2 minutes in the DTI group (P = 0.007). A trend was found toward complete tumor resection in the DTI group (P = 0.09). The sensitivity and specificity for predicting complete tumor resection were 88% and 62.5% for the non-DTI group and 100% and 80% for the DTI group, respectively. The area under the receiver operating characteristic curve was 0.720 in the non-DTI group and 0.966 in the DTI group (P = 0.041). CONCLUSIONS: Intraoperative navigated tractography shortened the time of awake neuro-oncological surgery and might provide help in performing complete tumor resection. Also, tractography used in the preoperative planning could be a useful tool for better prediction of complete tumor resection.

Glioblastoma treatment guidelines: Consensus by the Spanish Society of Neurosurgery Tumor Section. / Consenso sobre guías de tratamiento de los glioblastomas elaborado por el Grupo de Trabajo de Neurooncología (GTNO) de la SENEC.

INTRODUCTION: Glioblastoma (GBM) treatment starts in most patients with surgery, either resection surgery or biopsy, to reach a histology diagnose. Multidisciplinar team, including specialists in brain tumors diagnose and treatment, must make an individualize assessment to get the maximum benefit of the available treatments. MATERIAL AND METHODS: Experts in each GBM treatment field have briefly described it based in their experience and the reviewed of the literature. RESULTS: Each area has been summarized and the consensus of the brain tumor group has been included at the end. CONCLUSIONS: GBM are aggressive tumors with a dismal prognosis, however accurate treatments can improve overall survival and quality of life. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case.

Application of a Thrombin-Gelatin Matrix in the Management of Intractable Hemorrhage During Stereotactic Biopsy.

BACKGROUND: Few studies have been published about percutaneous techniques for management of surgical bed hemorrhage during a stereotactic biopsy, a serious complication that may affect patient outcome. We describe the injection of a thrombin-gelatin matrix through the biopsy cannula as an effective method to arrest surgical bed bleeding that does not respond to conventional methods of hemostasis. METHODS: We prospectively documented image-guided stereotactic brain biopsy procedures in 30 awake patients between July 2014 and July 2017 at our center. Among patients presenting with intractable surgical bed bleeding, a thrombin-gelatin matrix injection through the biopsy cannula was performed. Details of the injection technique, surgical outcome, and complications were recorded. RESULTS: Among 30 documented stereotactic brain biopsies, 3 (10%) had intractable surgical bed bleeding during the procedure. In all 3 cases, thrombin-gelatin matrix was injected, and an immediate arrest of hemorrhage was achieved. None of the patients required a craniotomy or further invasive measure to achieve hemostasis. No postoperative complications were recorded. CONCLUSIONS: Our preliminary results suggest that thrombin-gelatin matrix injection is a simple, safe, and effective stereotactic practice to manage persistent surgical bed bleeding that cannot be arrested by standard, conventional hemostatic methods.

Efficacy of Sphenopalatine Ganglion Radiofrequency in Refractory Chronic Cluster Headache.

BACKGROUND: In the literature, there are only short series of radiofrequency of the sphenopalatine ganglion (SPG) to treat chronic refractory cluster headache (CCHr) with variable results. Furthermore, there is no consensus on which methodology to use: radiofrequency ablation (RFA) or pulsed radiofrequency (PRF). METHODS: We conducted a prospective analysis of 37 patients with CCHr who underwent RFA or PRF of the SPG in our center between 2004 and 2015. RESULTS: The mean age of the patients was 40 years (range, 26-59 years). PRF was performed in 24 patients, and RFA was performed in 13 patients. A total of 5 patients (13.5%) experienced complete clinical relief of both pain and parasympathetic symptoms, 21 patients (56.8%) had partial and transient relief, and 11 patients (29.7%) did not improve. There was no evidence of significant superiority of one radiofrequency modality over the other (P = 0.48). There were no complications associated with the technique. The passage of time tended to decrease the efficacy of both techniques (P < 0.001). The mean follow-up was 68.1 months (range, 15-148 months). To our knowledge, this is the series with the largest number of patients and the longest follow-up period published in the literature. CONCLUSIONS: Radiofrequency of the SPG is a safe, fast, and partially effective method for the treatment of CCHr. Given its low rate of complications and its low economic cost, we think it should be one of the first invasive treatment options, prior to techniques with greater morbidity and mortality, such as neuromodulation.

Long-Term Safety and Performance of a Polymeric Clamplike Cranial Fixation System.

OBJECTIVE: After a craniotomy procedure to access the brain, neurosurgeons have several options to fix the bone flap to the skull. The aim of this study was to assess if a polymeric clamplike fixation system (Cranial LOOP) is a safe and reliable system that maintains over time an appropriate alignment of the bone flap. METHODS: This is an observational, retrospective, case series study of 60 patients who underwent a craniotomy and were subject to cranial bone flap fixation with the Cranial LOOP fixation system. Baseline clinical parameters, surgical variables, medical records, and all postoperative medical images available were reviewed to assess the bone flap alignment and potential adverse events. RESULTS: A total of 182 Cranial LOOPs were implanted in the 60 patients (56.01 ± 20.21 years, 55% women) included in the study. The cranial fixation system maintained a good bone flap alignment in 95% of the patients studied immediately after surgery and in up to 96.7% of them at the end of follow-up. No intraoperative complications were reported. An ulcer potentially related to a device was detected, which was solved without the need for device removal. No artifacts were observed in any of the 219 medical images analyzed. CONCLUSIONS: Cranial LOOP is a safe and reliable postoperative long-term cranial bone flap fixation system. This device can fix the bone flap after a wide range of craniotomy procedures, performed in multiple locations, and provides good bone flap alignment. Cranial LOOP does not interfere in patient follow-up through medical imaging.

[Neurophysiological monitoring options in brain tumour resections. Consensus statement from the Spanish Society of Neurosurgery's (SENEC) Neuro-oncology Working Group and the Spanish Society of Clinical Neurophysiology (SENFC)]. / Opciones de monitorización neurofisiológica en la resección de tumoraciones cerebrales. Documento de consenso entre el Grupo de Trabajo de Neurooncología de la Sociedad Española de Neurocirugía (SENEC) y la Sociedad Española de Neurofisiología Clínica (SENFC).

Brain tumours located in or in proximity to eloquent areas are a significant neurosurgical challenge. Performing this kind of surgery with neurophysiological monitoring to improve resections with reduced permanent focal neurological deficit has become widely accepted in the literature. However, how to conduct this monitoring, the exact definition of an eloquent area and whether to perform this surgery with the patient awake or asleep are still subject to rigorous scientific debate. Members of the Neuro-oncology Working Group (GTNO) of the Spanish Society of Neurosurgery (SENEC) and members of the Spanish Society of Clinical Neurophysiology (SENFC) have published a consensus statement to explain the different neurophysiological monitoring options currently available in awake and asleep patients to obtain better surgical resection without neurological deficits. An exhaustive review of the literature has also been conducted.

[Stimulation of the occipital nerve in the treatment of drug-resistant cluster headache]. / Estimulación del nervio occipital para la cefalea en racimos refractaria al tratamiento farmacológico.

AIM: To evaluate the occipital nerve stimulation therapy in as a treatment for drug-resistant cluster headache. PATIENTS AND METHODS: Prospective study of four patients, three males and one female. Mean age of 42 years. Patients complained of a cluster headache lasting between one and 16 years, with suboptimal control of the attacks with medication. In all cases octopolar electrodes were placed percutaneously in the occipital region bilaterally. Follow-up of 6 months. RESULTS: At 6 months, there was a 56% (range: 25-95%) reduction in the frequency, a 48.8% (range: 20-60%) decrease in the intensity and a 63.8% (range: 0-88.8%) reduction in the duration of the attacks. Worsening or progression of the illness was not observed in any case. All patients referred a 15.4% (range: 6-31.5%) improvement in their quality of life compared to their previous basal situation in SF-36. In all cases but one there was a significant reduction in the amount and dosage of medication required. Postoperative complications were not observed. All patients would recommend the procedure. CONCLUSIONS: Occipital nerve stimulation may be considered a safe and effective therapeutic option in the drug-resistant cluster headache. However, studies with more patients and a longer follow-up are required to evaluate the efficacy of the technique.

Sarcoma de Ewing primario epidural cervical / No disponible

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