Paediatric endoscopic endonasal middle skull base reconstruction: retrospective analysis of 78 patients treated in a single tertiary care paediatric center.

INTRODUCTION: Skull base pathologies in the paediatric population are rare and require treatment by multiple qualified specialists. The endoscopic endonasal approach has revolutionized surgical treatment because it is less invasive than existing treatments.The goal of this study was to retrospectively review our experience with the reconstruction of paediatric skull middle base defects and associated complications. MATERIALS AND METHODS: We analysed medical records from patients aged ≤ 18 years who were treated at our centre between 2013 and 2021. Patients treated with an endoscopic skull base approach and reconstruction, and who had complete clinical and radiological documentation and a minimum follow-up of 12 months, were included in the analysis. Personal data, reconstructive techniques, and complications were analysed. RESULTS: A total of 78 patients met the inclusion criteria and were enrolled in the study. Of these patients, 32 were male and 46 were female, and the mean age was 11.5 years. The main signs and symptoms were as follows: bitemporal hemianopsia in 53 cases, visual impairment in 23 cases, and headache in 30 cases. The most frequent aetiologies were craniopharyngioma (38 cases), pituitary adenoma (23 cases), and clivus chordoma (4 cases). All patients were treated via a pure endoscopic approach. For reconstruction, a multilayer technique was used in 18 cases, naso-septal flap in 43 cases, Gasket-Seal technique in 12 cases, and heterologous reconstruction in 5 cases. Only six patients presented a major complication: two had a postoperative cerebral spinal fluid leak, one developed a brain abscess, and three had diabetes insipidus.The mean follow-up period was 23.4 months.There were no statistically significant differences in postoperative CSF leak in relation to different reconstructive techniques. CONCLUSION: Endoscopic endonasal skull base surgery is a safe and effective treatment for paediatric middle skull base pathologies. Reconstruction techniques have a high success rate of 96.5-100%, and the rate of associated complications is < 3%.

Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Endoscopic Endonasal Treatment of Intra-Axial Ventral Brainstem Cavernomas: Case Experience and Literature Review.

INTRODUCTION: Cavernous malformations of the ventral brainstem are a challenging disease to treat. From an anatomical perspective, the best surgical options are endoscopic endonasal approaches. The first reports of their usage for this purpose date back to 2012. In this study, we gathered data on the subject, share our experience, and outline technical notes and tips for this surgery. CASE PRESENTATION: We report a 14-year-old female with a ventral pons cavernoma, treated using an endoscopic endonasal transclival approach and followed-up for 5.9 years. This is the longest reported follow-up for this condition to date. Written informed consent was obtained from the patient for publication of this case report and the accompanying images. DISCUSSION: An endoscopic endonasal transclival approach was used. The skull base was reconstructed using the multilayer grafting technique and a nasoseptal flap. There was no postoperative cerebrospinal fluid leakage. In a literature review, we identified 8 patients who were treated endoscopically: 1 transplanum-transtuberculum, 1 transtuberculum-transclival, and 6 transclival approaches were employed. Skull base closure was achieved using multilayer grafting and a nasoseptal flap in 4 cases, a gasket seal technique combined with nasoseptal flap in 3 cases and a periumbilical fat graft, fibrin sealant patch, and fibrin glue in 1 case. There were 2 cases of leakage, which resolved completely with revision surgery. CONCLUSION: Endoscopic surgery is a reliable alternative to traditional open surgery. It may be the preferred choice for intra-axial ventral brain cavernomas.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

Proton therapy: A therapeutic opportunity for aggressive pediatric meningioma.

Meningiomas are an extremely rare histology among pediatric brain tumors, and there is a shortage of literature on their management. Proton therapy is currently used safely and effectively for many types of both pediatric and adult cancer, and its main advantage is the sparing of healthy tissues from radiation, which could translate in the reduction of late side effects. We review the literature on radiotherapy and proton therapy for pediatric meningiomas and report clinical outcomes for two aggressive pediatric meningiomas we treated with protons. Proton therapy might be a safe and effective therapeutic option for this rare subgroup of tumors.

Dysembryoplastic neuroepithelial tumors: A single-institutional series with special reference to glutamine synthetase expression.

Dysembryoplastic neuroepithelial tumors (DNT) is a benign (World Health Organisation, WHO, grade I) glioneuronal tumor and it represent one of the most frequent neoplasm in patient affected by seizures. The epileptic neuronal activity can be determined by abnormal synchronization, excessive glutamate excitation and\or inadequate GABA inhibition. Increasing evidence suggests that the astrocytes might be involved in this process even if neurons play a relevant role. In particular astrocytes promote the clearance of glutamate, a potent excitatory neurotransmitter of the central nervous system. Indeed, elevated concentrations of extracellular glutamate may determine iper-excitability and seizures as well as other neurological disorders. So, astrocytes, converting glutamate into glutamine via the enzyme glutamine synthetase (GS), could play a protective anti-seizures role. In the present study, we analyzed the immunohistochemical expression of GS in 20 DNTs specimens documenting a constant immunoistochemical expression of GS in astrocytes of the lesional tissue and of the cerebral cortex.

Subependymal giant cell astrocytoma: a lesion with activated mTOR pathway and constant expression of glutamine synthetase.

Subependymal giant-cell astrocytoma (SEGA) is a rare tumor associated with tuberous sclerosis complex (TSC). TSC mainly involves the central nervous system (CNS) where SEGA, subependymal nodules, and cortical tubers may be present. First studies suggested the astrocytic nature of SEGA while successive studies demonstrated the mixed glio-neuronal nature. There are similarities between TSC-associated CNS lesions and type IIb focal cortical dysplasia (FCD). In all these pathologies, mammalian target of rapamycin (mTOR) pathway activation has been demonstrated. Recent data evidenced that balloon cells in FCD IIb express glutamine synthetase (GS). GS is involved in the clearance of glutamate. Cells expressing GS might exert an antiepileptic role. We evaluated by immunohistochemistry the glial fibrillary acidic protein (GFAP), neurofilaments (NF), and GS expression and the mTOR status (mTOR and phosphorylated ribosomal protein S6) in 16 SEGAs and 2 cortical tubers. Our purpose was to emphasize the mixed nature of SEGA and to further investigate the similarities between TSC-related CNS lesions (in particular SEGA) and FCD IIb. We confirm the glio-neuronal nature and the common activation of the mTOR pathway in SEGAs. In addition, we report for the first time that these tumors, analogously to FCD IIb, commonly express GS. Notably, the expression of mTOR, phosphorylated ribosomal protein S6, and GS was restricted to gemistocytic-like GFAP-negative cells. GS expression and mTOR pathway activation were also documented in cortical tubers. Further studies are necessary to understand the significance of GS expression in SEGAs as well as in cortical tubers.

Mini-Invasive Endoscope-Assisted Treatment of Metopic Craniosynostosis: 2-Dimensional Operative Video.

The surgical treatment of trigonocephaly has undergone significant evolution, with an increasing use of a minimally invasive technique. The endoscope-assisted metopic suturectomy is currently considered a valid surgical option for the correction of metopic craniosynostosis.1-5 In this video-article, we present our surgical technique performed on a 5-month-old patient with type III (Genitori's classification6) trigonocephaly. The computed tomography (CT) scan showed fusion of the metopic suture with bitemporal narrowing and hypotelorism. The patient underwent endoscope-assisted metopic suturectomy, the width of the suturectomy is 1 cm, and an Esmarch sheet was used to protect the dura mater while drilling. Bridging veins are coagulated under endoscopic vision. The suturectomy is considered complete when the nasal cartilages are exposed, deconnecting thus completely the orbits. The postoperative CT scan showed the extent of the suturectomy. The patient did not present any neurological deficit or complications after surgery and was discharged on postoperative day 2. No helmet was used postoperatively. The patient repeated a head CT at age 11 years after head trauma and was seen at consultation. Interestingly, once the bone gap created after the metopic suturectomy reossifies, the frontal sinus develops normally. The long-term result was quite satisfying. The advantages of the mini-invasive technique consist in a smaller surgical scar, lower blood loss, shorter surgical time, and shorter hospital stay with good long-term results. The parents provided written consent for the publication of the patient's picture, the institutional research board approved the submission of this video article. In the video, the tips, tricks, and pitfalls of the technique are discussed.

Vascular complications in craniopharyngioma-resected paediatric patients: a single-center experience.

Background: Craniopharyngioma (CP), although slow growing and histologically benign, has high morbidity, mostly related to hypothalamus-pituitary dysfunction and electrolyte imbalance. Increased risk of vascular complications has been described. However, data are still poor, especially in the paediatric population. The aim of our study was to evaluate the occurrence, timing, and predisposing factors of deep venous thrombosis (DVT) and other vascular alterations in neurosurgical paediatric CP patients. Materials and Methods: In a single-centre, retrospective study, we investigated 19 CP patients (11 males, 8 females, mean age 10.5 ± 4.3 years), who underwent neurosurgery between December 2016 and August 2022, referred to Meyer Children's Hospital IRCCS in Florence. Results: Five patients (26.3%) presented vascular events, which all occurred in connection with sodium imbalances. Three DVT (two with associated pulmonary embolism, in one case leading to death) developed in the post-operative period, most frequently at 7-10 days. Elevated D-dimers, a reduced partial activated thrombin time and a prolonged C-reactive protein increase were highly related to thrombotic vascular events. One case of posterior cerebral artery pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting. Superficial vein thrombophlebitis was a late complication in one patient with other predisposing factors. Conclusion: CP patients undergoing neurosurgery are at risk of developing DVT and vascular alterations, thus careful follow-up is mandatory. In our study, we found that the phase of transition from central diabetes insipidus to a syndrome of inappropriate antidiuretic hormone secretion may be a period of significant risk for DVT occurrence. Careful vascular follow-up is mandatory in CP-operated patients.

Leat-associated seizures the possible role of EAAT2, pyruvate carboxylase and glutamine synthetase.

BACKGROUND: Drug-resistant epilepsy is a common condition in patients with brain neoplasms. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathogenetic mechanisms, the increase in glutamate concentration has been proposed. Glutamate transporters, glutamine synthetase and pyruvate carboxylase are involved in maintaining the physiological concentration of glutamate in the intersynaptic spaces. In our previous research on angiocentric gliomas, we demonstrated that all tumors lacked the expression of the main glutamate transporter EAAT2, while the expression of glutamine synthetase and pyruvate carboxylase was mostly preserved. METHODS: In the present study, we evaluated the immunohistochemical expression of EAAT2, glutamine synthetase and pyruvate carboxylase in a heterogeneous series of 25 long-term epilepsy-associated tumors (10 dysembryoplastic neuroepithelial tumors, 7 gangliogliomas, 3 subependymal giant cell astrocytomas, 3 rosette forming glioneuronal tumors, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). In order to evaluate the incidence of variants in the SLC1A2 gene, encoding EAAT2, in a large number of central nervous system tumors we also queried the PedcBioPortal. RESULTS: EAAT2 protein expression was lost in 9 tumors (36 %: 3 dysembryoplastic neuroepithelial tumors, 1 ganglioglioma, 3 subependymal giant cell astrocytomas, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). Glutamine synthetase protein expression was completely lost in 2 tumors (8 %; 1 ganglioglioma and 1 diffuse astrocytoma MYB- or MYBL1-altered). All tumors of our series but rosette forming glioneuronal tumors (in which neurocytic cells were negative) were diffusely positive for pyruvate carboxylase. Consultation of the PedcBioPortal revealed that of 2307 pediatric brain tumors of different histotype and grade, 20 (< 1%) had variants in the SLC1A2 gene. Among the SLC1A2-mutated tumors, there were no angiocentric gliomas or other LEATs CONCLUSIONS: In conclusion, unlike angiocentric gliomas where the EAAT2 loss is typical and constant, the current study shows the loss of EAAT2 expression only in a fraction of the LEATs. In these cases, we may hypothesize some possible epileptogenic role of the EAAT2 loss. The retained expression of pyruvate carboxylase may contribute to determining a pathological glutamate excess unopposed by glutamine synthetase that resulted expressed to a variable extent in the majority of the tumors. Furthermore, we can assume that the EAAT2 loss in brain tumors in general and in LEATs in particular is more conceivably epigenetic.

Is endoscope-assisted strip craniectomy the future of metopic suture craniosynostosis treatment? An 11-year experience with 62 patients.

OBJECTIVE: Endoscopic mini-invasive treatment for sporadic trigonocephaly is becoming a widely accepted surgical treatment. In most centers this treatment is performed in association with postoperative helmeting. The aim of the present study was to review and report the authors' 11-year experience of endoscope-assisted metopic suturectomy for treatment of 62 trigonocephaly patients without helmet use. METHODS: For this retrospective study, clinical data of 62 consecutive pediatric patients (age 3-8 months) were obtained from the data bank of the "Anna Meyer" Children Hospital. These patients had been diagnosed with trigonocephaly (type II and III) and undergone surgery performed with a mini-invasive endoscopic technique during the period from January 2011 to January 2022. No helmet was used postoperatively in these patients, and they were evaluated through craniometric measurements, pre-/postoperative photographs, and parents' impressions, as well as thorough clinical examinations during follow-up appointments. RESULTS: The mean patient follow-up period was 6 ± 1.3 years. The female/male ratio was 1:2; 52% of the patients presented with type II trigonocephaly and the remaining patients with type III. The mean age at surgery was 153 ± 44 days (5 ± 1.5 months, range 3-8 months). In 92% of the patients the surgical outcome was defined as good to excellent. However, 4 patients presented with an unsatisfactory outcome, including 1 patient with a CSF collection requiring surgical repair 2 months after the first surgery and 1 patient who developed infection of the surgical wound and needed a second surgery. In the latter patient the outcome was evaluated as satisfactory, and no sequelae regarding the infection were encountered during follow-up. CONCLUSIONS: According to the authors' experience, endoscopic metopic suturectomy alone, without the use of a helmet, is a valid surgical option for trigonocephaly treatment, and its application can be considered in patients of older age groups (up to 8 months). Thus, in the right patient selection context, this technique represents the treatment of choice.

Pediatric High Grade Glioma Classification Criteria and Molecular Features of a Case Series.

Pediatric high-grade gliomas (pHGGs) encompass a heterogeneous group of tumors. Three main molecular types (H3.3 mutant, IDH mutant, and H3.3/IDH wild-type) and a number of subtypes have been identified. We provide an overview of pHGGs and present a mono-institutional series. We studied eleven non-related pHGG samples through a combined approach of routine diagnostic tools and a gene panel. TP53 and H3F3A were the most mutated genes (six patients each, 54%). The third most mutated gene was EGFR (three patients, 27%), followed by PDGFRA and PTEN (two patients each, 18%). Variants in the EZHIP, MSH2, IDH1, IDH2, TERT, HRAS, NF1, BRAF, ATRX, and PIK3CA genes were relatively infrequent (one patient each, 9%). In one case, gene panel analysis documented the presence of a pathogenic IDH2 variant (c.419G>A, p.Arg140Gln) never described in gliomas. More than one-third of patients carry a variant in a gene associated with tumor-predisposing syndromes. The absence of constitutional DNA did not allow us to identify their constitutional origin.

Primary Intracerebral Alveolar Soft Part Sarcoma: Report of a Case and Review of the Literature.

Alveolar soft part sarcomas (ASPSs) are rare malignant tumors representing ∼1% of all soft tissue sarcomas. Most ASPS occurring in the central nervous system are metastases. In contrast, primary intracranial ASPSs are extremely rare and only 8 cases have been previously reported in English literature. Here, we report a case of primary alveolar soft part sarcoma in a 16-year-old female patient with no evidence of primary extracranial tumors. Histologically this case fulfilled the criteria of ASPS, and a molecular confirmation has been archived. To date, only 9 primary intracranial ASPS cases, including ours, have been reported in the literature. This report highlights the clinical and pathological characteristics, differential diagnosis, and molecular analysis of primary ASPS of the central nervous system.

Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study.

Medulloblastoma is the most common malignant brain tumor in children. Even if current treatment dramatically improves the prognosis, survivors often develop long-term treatment-related sequelae. The current radiotherapy standard for medulloblastoma is craniospinal irradiation with a boost to the primary tumor site and to any metastatic sites. Proton therapy (PT) has similar efficacy compared to traditional photon-based radiotherapy but might achieve lower toxicity rates. We report on our multi-centric experience with 43 children with medulloblastoma (median age at diagnosis 8.7 years, IQR 6.6, M/F 23/20; 26 high-risk, 14 standard-risk, 3 ex-infant), who received active scanning PT between 2015 and 2021, with a focus on PT-related acute-subacute toxicity, as well as some preliminary data on late toxicity. Most acute toxicities were mild and manageable with supportive therapy. Hematological toxicity was limited, even among HR patients who underwent hematopoietic stem-cell transplantation before PT. Preliminary data on late sequelae were also encouraging, although a longer follow-up is needed.

Management of orbital and brain complications of sinusitis: A practical algorithm.

The aim of this work was to present a practical management algorithm for orbital and brain complications of sinusitis. According to the inclusion criteria, a sample of 68 patients was collected between 2008 and 2018 (39 males and 29 females). Among them, 44 were adults, with a mean age of 50.46 years, and 24 were pediatric patients, with a mean age of 10.33 years. Oral or intravenous antibiotic therapy was administered to all patients. Pharmacological resolution was observed in 14 cases. Early surgical treatment within 48 hours was necessary in 10 cases. Surgery consisted of abscess drainage, associated or not with functional endoscopic sinus surgery. Delayed surgery within 15-30 days was performed in 44 patients. The core procedure was functional endoscopic sinus surgery. Subsidiary procedures were abscess drainage, tooth extraction or cranial base repair. The combination of two or more of these procedures was case selected. Median follow-up was of 46.36 months. Sinusitis complications necessitate rapid diagnosis and prompt treatment. Antibiotic therapy alone is enough for mistreated rhinosinusitis with no anatomical predisposing factor. Surgery is mandatory for altered nasal and paranasal sinus anatomy or odontogenic infections.

Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase.

PURPOSE: Our purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces. METHODS: We evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas. RESULTS: EAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %). CONCLUSION: The net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives.

Current Practice in Preoperative Virtual and Physical Simulation in Neurosurgery.

In brain tumor surgery, an appropriate and careful surgical planning process is crucial for surgeons and can determine the success or failure of the surgery. A deep comprehension of spatial relationships between tumor borders and surrounding healthy tissues enables accurate surgical planning that leads to the identification of the optimal and patient-specific surgical strategy. A physical replica of the region of interest is a valuable aid for preoperative planning and simulation, allowing the physician to directly handle the patient's anatomy and easily study the volumes involved in the surgery. In the literature, different anatomical models, produced with 3D technologies, are reported and several methodologies were proposed. Many of them share the idea that the employment of 3D printing technologies to produce anatomical models can be introduced into standard clinical practice since 3D printing is now considered to be a mature technology. Therefore, the main aim of the paper is to take into account the literature best practices and to describe the current workflow and methodology used to standardize the pre-operative virtual and physical simulation in neurosurgery. The main aim is also to introduce these practices and standards to neurosurgeons and clinical engineers interested in learning and implementing cost-effective in-house preoperative surgical planning processes. To assess the validity of the proposed scheme, four clinical cases of preoperative planning of brain cancer surgery are reported and discussed. Our preliminary results showed that the proposed methodology can be applied effectively in the neurosurgical clinical practice both in terms of affordability and in terms of simulation realism and efficacy.