GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. METHODS: We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. RESULTS: Here, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. INTERPRETATION: Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023;94:745-761.

Intracranial Solitary Fibrous Tumour Management: A French Multicentre Retrospective Study.

BACKGROUND: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs. METHODS: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS). RESULTS: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03). CONCLUSION: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

Descriptive Epidemiology of Ependymal Tumors in Gironde, France: Results from the Gironde Registry for the 2000-2018 Period.

BACKGROUND: The Gironde Central Nervous System (CNS) Tumor Registry, in collaboration with the French National Cancer Institute, is the largest population-based registry focused exclusively on primary CNS tumors in France and represents a population of 1.62 million. This report focuses on ependymal tumors to refine current knowledge and provide up-to-date data on the epidemiology of these rare tumors. MATERIAL AND METHODS: All of the ependymal tumors were extracted from the Gironde CNS Tumor Registry for the years 2000-2018. Demographic and clinical characteristics, incidence rates, and time trends as well as survival outcomes were analyzed. RESULTS: One hundred forty-four ependymal tumors were retrieved, which represented 2.3% of all the CNS tumors recorded in the same period. Histological subtype was significantly dependent on age and topography in the CNS. The median age at diagnosis was 46 years. The annual incidence rates varied between 0.15/100,000 (2004) and 0.96/100,000 (2016), with a significant increase over the study period by 4.67% per year. Five-year and 10-year OS rates were 87% and 80%, respectively. CONCLUSION: An increase in the incidence of ependymal tumors was observed over the past two decades. Further studies are needed to confirm this result and provide etiological clues.

A case series of percutaneous transforamen ovale biopsies in cavernous sinus lesions.

BACKGROUND: The majority of cavernous sinus lesions are meningiomas, for which treatment (fractioned radiotherapy or radiosurgery), if indicated, is usually initiated upon image-based diagnosis. However, this region can be affected by a wide variety of pathological processes and the risk of misdiagnosis exists. As pathological diagnosis can be obtained by biopsy through the foramen ovale in selected cases, we asked the question as to whether systematically performing this procedure before treatment would provide additional, relevant diagnostic information. METHODS: All the cases referred to our department between January 2008 and December 2019 for cavernous sinus lesions that were considered for treatment and anatomically suitable for transforamen ovale biopsy were included. Outcomes and subsequent treatment or follow-up data were collected. RESULTS: Thirty-five patients were included. Twenty-six were highly suspected to have meningioma or schwannoma at imaging, among whom biopsy allowed diagnosis confirmation in 17 cases (65%). For the nine patients for whom biopsy was indicated upon suspected malignancy or inflammatory disease on imaging, biopsy revealed three meningiomas and one lymphoma and was not contributory in five cases (56%), three of which underwent open surgery. Three patients (8.5%) had persistent neuralgia at the last follow-up. CONCLUSIONS: When cavernous sinus meningioma or schwannoma is highly suspected upon predefined imaging criteria by an experienced neuroradiologist, invasive exploration before treatment does not seem to be indicated. Otherwise, transforamen ovale biopsy might be consider in selected cases as a minimally invasive option to obtain pathological analysis.

Combining 3'-Deoxy-3'-[18F] fluorothymidine and MRI increases the sensitivity of glioma volume detection.

OBJECTIVE: 3'-Deoxy-3'-[18F] fluorothymidine (18F-FLT) is a marker of cell proliferation and displays a high tumor-to-background ratio in brain tumor lesions. We determined whether combining 18F-FLT PET and MRI study improves the detection of tumoral tissue compared to MRI alone and whether 18F-FLT uptake has a prognostic value by studying its association with histopathological features. METHODS: Thirteen patients with a supratentorial malignant glioma were recruited and scheduled for surgery. The tumor volume was defined in all patients on both 18F-FLT PET and MRI images. The images were coregistered and uploaded onto a neuronavigation system. During surgery, an average of 11 biopsies per patient were taken in regions of the brain that were positive to one or both imaging modalities, as well as from control peritumoral regions. The standardized uptake values (SUVs) of each biopsy region were correlated to histopathological data (i.e., proliferation index and number of mitoses) and the SUV values of high and low-grade samples were compared. RESULTS: Out of a total of 149 biopsies, 109 contained tumoral tissue at histopathological analysis. The positive predictive value was 93.1% for MRI alone and 78.3% for MRI and PET combined. In addition, 40% of the biopsy samples taken from areas of the brain that were negative at both PET and MRI had evidence of malignancy at pathology. The SUV values were not significantly correlated to either the proliferation index or the number of mitoses, and could not differentiate between high- and low-grade samples. CONCLUSION: In patients with newly diagnosed glioma, a combination of MRI and 18F-FLT-PET detects additional tumoral tissue and this may lead to a more complete surgical resection. Also, the addition of a negative PET to a negative MRI increases the negative predictive value. However, 18F-FLT still underestimated the margins of the lesion and did not correlate with histopathological features.

Secondary Reconstruction of Calvarial Defects by Using Free Flap: Report of Consecutive Cases and Analysis of Strategy.

INTRODUCTION: Multiplication of incisions and/or radiotherapy on the scalp, lead to skin necrosis and chronic osteitis. In this situation, reconstructive surgery can be useful to cover complex lack of tissue. MATERIALS AND METHODS: The 5 patients were treated with the neurosurgery department of our hospital. The procedure included debridement of the infected calvarian bone and tissues and coverage by free antebrachial flap. A 2 stages skin graft, using a dermal regeneration template, or direct closure was used for the donor site. Evaluation of flap quality and donor site morbidity was done during hospitalization and 3 months after the procedure. RESULTS: The procedure was achieved on 5 patients. All the patients were healed 3 months after surgery. For 1 patient, a second procedure was done in emergency for anastomosis revision. There was non-complication concerning the donor site. All the patients healed with a good coverage. CONCLUSION: Treatment of calvarian bone necrosis needs a very good and reliable coverage, such as free flap can provide. In our opinion, the antebrachial free flap is an interesting option, despite the fact that it is still underused for scalp coverage.

Contralateral Transcranial Approach to Tuberculum Sellae Meningiomas: Long-Term Visual Outcomes and Recurrence Rates.

BACKGROUND: One of the most challenging aspects of the surgical treatment of tuberculum sellae meningioma is to control the involvement of the inferomedial side of the optic nerve, which is not directly visualized by an ipsilateral approach and thus requires optic nerve mobilization. METHODS: Between 2003 and 2017, 21 consecutive patients were operated on using this approach. The surgical technique is described and the visual outcomes, resection and recurrence rates, and complications are analyzed. RESULTS: Twenty patients were included, with a median follow-up of 5.6 years. Regarding visual outcomes, among the 19 patients who had a visual impairment before surgery, 14 (74%) improved, 2 were stabilized (10%), and 2 (10%) showed a worsening of the most-compromised optic nerve and 1 (5%) of the less-compromised optic nerve. Gross total resection was achieved in 18 patients (90%) and 1 patient experienced recurrence 10 years after the initial surgery. CONCLUSIONS: This approach allowed lower mobilization of the compromised optic nerve, better preservation of the vascularization of the visual pathways, and direct access to the inferomedial side of the optic nerve.

Usefulness of Motor-Evoked Potentials Monitoring for Neurosurgical Treatment of an Unusual Distal Anterior Choroidal Artery Aneurysm.

A 35 years old woman presented with an acute meningeal syndrome following an intra ventricular haemorrhage without subarachnoid haemorrhage. The angiography demonstrated a 6 mm partially thrombosed saccular aneurysm at the plexal point of the right anterior choroidal artery (AChoA). It was surgically approached inside the ventricle through a trans-temporal corticotomy. The aneurysm was excised after distal exclusion of the feeding artery under motor-evoked potentials monitoring. Of the 19 cases of distal AChoA aneurysm neurosurgical treatment, this is the only one performed under electrophysiology monitoring, a simple and safe method to detect and prevent motor tract ischemia. We discuss this rare case, along with a comprehensible review of the literature of the previous surgical cases of distal AChoA aneurysms.

Oculomotor nerve palsy induced by internal carotid artery aneurysm: prognostic factors for recovery.

BACKGROUND: Aneurysms at the posterior face of the internal carotid artery can lead to oculomotor nerve palsy (ONP) with an uncertain prognosis of recovery post-treatment. The aim of this study was to define the prognostic factors for ONP recovery, with particular interest in treatment modality (surgery or endovascular techniques). METHOD: A literature review was performed to select the most pertinent prognostic factors. A retrospective study was then performed to determine whether these factors had significantly modified the prognosis of ONP recovery in our series of patients. RESULTS: In the literature, factors linked to poorer outcome were age, vascular risk factors, initial ONP severity and delay before treatment; better recovery was associated with surgical treatment. Between 2000 and 2013, 23 consecutive patients were treated in our department for ONP-inducing aneurysms: 14 by endovascular embolization and 9 by surgical clipping and aneurysm puncture. Mean follow-up was 48.8 months. After treatment, overall recovery occurred in 87% of cases, always within 6 months. Apart from treatment modality, no selected prognostic factor significantly modified the quality or timing of ONP recovery. In the endovascular group, four patients recovered completely, seven partially and three did not recover. In the surgical group, seven patients recovered completely and two partially. Surgery was significantly associated with a more complete and earlier ONP recovery (p < 0.05). CONCLUSIONS: Surgery was associated with a more complete and earlier ONP recovery as compared to endovascular treatment, confirming the results of previous studies. However, conclusions must be confirmed by a prospective randomized study.

Association of elevated glial expression of interleukin-1beta with improved survival in patients with glioblastomas multiforme.

OBJECT: The aim of this study was to investigate the association of interleukin-1beta (IL-1beta) expression with improved survival in patients with glioblastomas multiforme (GBMs). Immune and vascular host-tumor interactions play a pivotal role in the control of tumor development, and inflammatory mechanisms may participate in the host's defense against tumor cells. Expression of proinflammatory cytokines and of inducible nitric oxide synthase (iNOS) has been noted in various types of malignant tumors, raising the possibility that endogenous expression of cytokines and the resulting cytotoxic action of sustained NO production play a role in the control of tumor growth. Indeed, human GBMs express variable amounts of iNOS. METHODS: In this study, the expression of iNOS and of cytokines known to upregulate IL-1beta, tumor necrosis factor-alpha, interferon-gamma or downregulate iNOS transcription (IL-10, transforming growth factor [TGF]beta1, and TGFbeta2) were measured using reverse transcription-polymerase chain reaction with competitor DNA in 39 samples of human GBM. The iNOS level in GBM was positively correlated with IL-1beta messenger (m)RNA, but not with the other cytokines tested. Immunocytochemical double labeling revealed that both anti-iNOS immunoreactivity and anti-IL-1beta immunoreactivity colocalized with glial fibrillary acidic protein immunoreactivity in GBM. Some macrophage/microglial cells also expressed iNOS, but not IL-1beta. Comparison of biological data with clinical parameters indicated that the survival duration was enhanced when levels of IL-1beta mRNA were elevated or when levels of TGFbeta2 were low, but was independent of the level of iNOS mRNA within the tumor. CONCLUSIONS: Taken together, these data indicate that the proinflammatory cytokine IL-1beta produced within GBM by glial-derived cells has a negative impact on tumor growth through a mechanism independent of iNOS induction.